library(tidyverse)
library(rethinking)
library(dagitty)
library(knitr)
library("ggdag")
library("ggrepel")

library(INLA)
library(knitr)
library(stringr)
library("patchwork")
library("ghibli")

MENSAJE PARA MAMA

EPIDEMIOLOGICAL CONCEPTS

MEASURES OF DISEASE FREQUENCY

MORBIDITY

prevalence

Proportion of the population affected at time t = snapshot of disease.

Units: 0-1 or 0-100%

\[\frac{cases\:at\:time\:t\:(new + existing)}{total\:population\:at\:time\:t}\] Risk of being a case.

\[prevalence = incidence * duration\] It’s a bad measure of risk because it depends on the duration of disease. Chronic diseases will have high prevalnce, and very fatal diseases will have low prevalence, regardless of the incidence.

  • point prevalence: prevalence at a given timepoint t

\[\frac{cases\:at\:time\:t\:(new + existing)}{total\:population\:at\:time\:t}\]

  • period prevalence: prevalence at any given timepoint during a time period t

\[\frac{cases\:observed\:over\:period\:t\:(new + existing)}{total\:population\:at\:midpoint\:of\:period\:t}\]

incidence

Proportion of the population at risk of being affected that does become affected during a time period t. cases/population * time at risk

\[\frac{new\:cases\:observed\:over\:period\:t}{total\:population\:at\:risk\:during\:period\:t}\]

Risk of becoming a case.

\[\frac{cases}{population*time\:at\:risk}\] It measures risk because it measures events or transitions from affected to not affected state.

  • cumulative incidence

The population at risk is a crude measure of the population at risk at the beginning of the time period. It assumes a static population at risk.

Units: 0-1 or 0-100% per time interval.

\[\frac{new\:cases\:observed\:over\:period\:t}{total\:population\:at\:risk\:at\:start\:of\:time\:period\:t}\] Measures average risk. Is apt for short time-periods or static populations.

  • incidence density rate

The population at risk is the sum of all the disease-free/ at risk time periods for each individual. It assumes the risk of each person in the population does not change over time.

Units: 0- \(\infty\) cases/population-time

\[\frac{new\:cases\:observed\:over\:period\:t}{total\:population-time}\] Measures risk by taking into account the time elapsed before disease occured for each individual, thus it also measures the speed at which disease occurs at a certain timepoint. Is apt for prolonged time-periods or dynamic populations.

To calculate population-time:

  • sum all the disease-free time for each individual.
  • estimate:
    • count the population-time midway through the time period
    • average the population-time at the beginning and the end of the period.

attack rate

Proportion of the exposed individuals that becomes affected during a time period t.

\[\frac{cases}{exposed}\]

Relationship between incidence and prevalence. Gordis

MORTALITY

mortality rate

Speed of death in time t.

Measures risk: good measure when disease is mild, bad measure when disease is very deadly and the case-fatality is high.

\[\frac{deaths\:over\:period\:t}{total\:population\:at\:risk\:during\:time\:period\:t}\]

  • crude mortality rate

overall deaths

\[\frac{deaths\:over\:period\:t}{total\:population\:at\:risk\:during\:time\:period\:t}\]

  • specific mortality rate

deaths in a specific subgroup (age, sex, diseased with a certain disease)

\[\frac{deaths\:in\:subgroup\:over\:period\:t}{population\:at\:risk\:in\:subgroup\:during\:time\:period\:t}\]

case fatality rate

Proportion of the individuals that become affected by disease X who die during a time period t.

Measures disease severity

\[\frac{deaths}{cases}\]

proportionate mortality

Fraction of all the deaths caused by disease X

\[\frac{deaths\:from\:disease\:X}{all\:deaths}\]

RATES

crude

overall population

adjusted

adjusted rates controlling for confounding factors to remove the effect of that factor

  • direct

Apply the specific subgroup rates of each population to a standard population and calculate the rate on the standard population.

direct adjusted example from Gordis

  • indirect

Compare populations: subgroup vs general

SMR = Strandard Mortality Ratio \[SMR= \frac{Observed}{Expected}\]

Expected: Apply the general population rates to each specific subgroup and add all the cases Observed: add all the observed cases in each specific subgroup

indirect adjusted example from Gordis

DIAGNOSTIC TEST EVALUATION AND SCREENING TESTS

test precision: ability to produce consistent results when repeated under the same conditions:

  • repeatability: consistency of test results under same condition except time

  • reproducibility: consistency of test results under different conditions

Disease + Disease - Total
Test + a = P[T(+) & D(+)] = true positive b = P[T(+) & D(-)] = false positive a+b = P[T(+)] = test positive
Test - c = P[T(-) & D(+)] = false negative d = P[T(-) & D(-)] = true negative c+d = P[T(-)] = test positive
Total a+c = P[D(+)] = disease positive b+d = P[D(-)] = disease negative 1=a+b+c+d = total

TEST PERFORMANCE CHARACTERISTICS

sensitivity

Probability that test is positive given that the individual is diseased

\[P(T^+|D^+)= \frac{P(T^+ \cap D^+)}{P(D^+)}\]

specificity

Probability that test is negative given that the individual is not diseased

\[P(T^-|D^-)= \frac{P(T^- \cap D^-)}{P(D^-)}\]

TRADE-OFF

In continuous results, the cut-off that for a positive test can determine the specificiity and sensitivity of the test, and should be chosen depending on the purpose.

  • lower threshold:increases the sensitivity but decreases the specificity by increasing false positives

  • higher threshold:increases the specificity but decreases the sensitivity by increasing false negatives

ROC curve: Receiver Operating Characteristic (ROC) curve: is a graphic portrayal of the sensitivity-specificity trade-off as cut-off values vary.

AUC: is the area under the curve.

  • The AUC of a useful test must be \(>\) 0.5
    • area of the total square = 1
    • area of a random process = 0.5
    • 1 - 0.5 = 0.5
  • It can also be defined as the probability that a randomly selected diseased individual will have a higher test value that a randomly selected non-diseased individual.

Example: AUC = 0.9 : a randomly selected diseased individual will have a higher test value that a randomly selected non-diseased individual 90 % of the time.

  • It can also be defined as the:
    • average sensitivity across all possible 1- specificity values
    • average true positive ratio across all possible false positive ratio

Youden’s index= J-statistic: sensitivity + specificity - 1 = true positive ratio - false positive ratio

likelihood ratio negative

likelihood that a non-diseased individual will test negative vs an individual that is not diseased = the odds that a negative test would be expected in a diseased individual

\[\frac{P(T^-|D^+)}{P(T^-|D^-)}= \frac{1-P(T^+ | D^+)}{P(T^- | D^-)}= \frac{1-sensitivity}{specificity}\]

likelihood ratio positive

likelihood that a diseased individual will test positive vs an individual that is not diseased = the odds that a positive test would be expected in a diseased individual

\[\frac{P(T^+|D^+)}{P(T^+|D^-)}= \frac{P(T^+ | D^+)}{1-P(T^- | D^-)}= \frac{sensitivity}{1-specificity}\]

CHARACTERISTICS OF LIKELIHOOD RATIOS

  1. independent from prevalence

  2. can be used to shorten list of diagnostic possibilities. If LR = 1, the test provides no information on disease status.

POST-TEST PROBABILITIES

once you have a test result, how likely is it that you have disease?

ppv : positive predictive value

Probability that the individual is diseased given that the test was positive

\[P(D^+|T^+)= \frac{P(T^+ \cap D^+)}{P(T^+)}\]

npv : negative predictive value

Probability that the individual is not diseased given that the test was negative

\[P(D^-|T^-)= \frac{P(T^- \cap D^-)}{P(T^-)}\]

WHAT AFFECTS PREDICTIVE VALUES ?

  • prevalence

The ppv of a test increased and the npv of a test decreases as the prevalence of the disease in the population increases.

Gordis

  • specificity: for the same prevalence, a test with higher specificity has higher ppv.

    • in common diseases: the sensitivity has a larger effect on the ppv because it decreases the false positives.

    • in rare diseases: the specificity has a larger effect on the ppv because it decreases the false negatives.

    Because disease are usually infrequent and there are more healthy individuals than diseases individuals, any increase in specifcity that affects the number of healthy individuals has a greater effect than finding diseased individuals.

Gordis

TO IMPROVE PREDICTIVE VALUES:

  • test high-risk populations

  • increase the cut-off to increase specificity.

TEST PRECISION

Oberver A Test + Oberver A Test - Total
Oberver B Test + a b a+b
Oberver B Test - c d c+d
Total a+c b+d 1=a+b+c+d = total

kappa statistic

\[\kappa= \frac{P_O-P_E}{1-P_E}\]

contrasts observed agreement with the agreement that would have been observed by chance alone.

  • percent agreement between 2 observers: \(P_O = \frac{a+d}{a+b+c+d}\)

  • expected agreement by chance: % \(P_E = \frac{[P(T_{ObserverA}^+) * T_{ObserverB}^+] + [P(T_{ObserverA}^-) * T_{ObserverB}^-]}{total}=\frac{\frac{a+c}{a+b+c+d}*(a+b) + \frac{b+d}{a+b+c+d}*(c+d)}{a+b+c+d}\)

Example: Pathologist A read 60% of all 75 slides (45 slides) as being grade II and 40% (30 slides) as grade III. If his or her readings had used criteria independent of those used by pathologist B (e.g., if pathologist A were to read 60% of any group of slides as grade II), we would expect that pathologist A would read as grade II both 60% of the slides that pathologist B had called grade II and 60% of the slides that patholo- gist B had called grade III. Therefore, we would expect that 60% (26.4) of the 44 slides called grade II by pathologist B would be called grade II by pathologist A and that 60% (18.6) of the 31 slides called grade III by pathologist B would also be called grade II by pathologist A. Of the 31 slides called grade III by pathologist B, 40% (12.4) would also be classified as grade III by pathologist A.

\(P_E = \frac{[0.6 * 44] + [0.4 * 31]}{75}= \frac{26.4+ 12.4}{75}= 51.7\)

Gordis

  • -1 = perfect disagreement
  • 0 = agreement expected by chance
  • 1 = perfect agreement

Kappa is affected by prevalence, and therefore can only be used within studies but not across studies.

MULTIPLE TEST

sequential

An individual is considered disease positive if the individual tests positive on both tests.

This method is often used for screening

more opportunities to test negative lead to:

  • decrease in sensitivity (\(P(T^+|D^+)\)): a diseased individual has more opportunities to test negative

  • increase in specificity (\(P(T^-|D^-)\)): a non-diseased individual has more opportunities to be correctly diagnosed as negative

  • increase in ppv (\(P(D^+|T^+)\)): there are fewer false positive

  • decrease in npv (\(P(D^-|T^-)\)): there are more false negatives

EXAMPLE

  • Original values:

sensitivity (\(P(T^+|D^+)= 0.70\)

specificity \(P(T^-|D^-) = 0.80\)

ppv \(P(D^+|T^+)= 0.16\)

npv \(P(D^-|T^-) = 0.98\)

Gordis

  • After sequential testing: 505 individuals are positive in both tests

net sensitivity (\(P(T^+|D^+)= 315/500= 0.63\)

net specificity \(P(T^-|D^-) = (1710+7600)/9500= 0.98\)

net ppv \(P(D^+|T^+)= 350/505= 0.62\)

net npv \(P(D^-|T^-)= (1710+7600)/ (7750+1745) = 0.98\)

simultaneous

An individual is considered disease positive if the individual tests positive on either tests.

more opportunities to test positive lead to:

  • increase in sensitivity (\(P(T^+|D^+)\)): a diseased individual has more opportunities to test positive

  • decrease in specificity (\(P(T^-|D^-)\)): a non-diseased individual has more opportunities to be incorrectly diagnosed as positive, that is there are more false positives

  • decrease in ppv (\(P(D^+|T^+)\)): there are more false positives

  • increase in npv (\(P(D^-|T^-)\)): if an individual is negative on both tests, it is more likely not to be diseased

EXAMPLE

  • Original values:

TEST A

sensitivity test A (\(P(T^+|D^+)= 0.80\)

specificity test A \(P(T^-|D^-) = 0.60\)

ppv test A \(P(D^+|T^+)= 0.33\)

npv test A \(P(D^-|T^-) = 0.92\)

TEST B

sensitivity test B (\(P(T^+|D^+)= 0.90\)

specificity test B \(P(T^-|D^-) = 0.90\)

ppv test A \(P(D^+|T^+)= 0.69\)

npv test A \(P(D^-|T^-) = 0.97\)

Gordis

  • After simultaneus testing:

net sensitivity

\(T_A^+ =80\%sensitivity * total = 0.8*200= 160\)

\(T_B^+ =90\%sensitivity * total = 0.9*200= 180\)

\(T_{AB}^+ =90\%sensitivity * 80\%sensitivity* total = 0.8* 0.9*200= 144\)

or \(P(A)+P(B)-P(A\cap B) = 0.8+0.9+ (0.8*0.9) = 0.98\)

\(T_{only A}^+ = 160-144=16\)

\(T_{only B}^+ = 180-144=36\)

Gordis net specificity

\(T_{AB}^-= 0.6*0.9 = 0.54\)

Gordis

net ppv = \(196/564=0.35\)

net npv = \(432/436=0.99\)

CAUSAL INFERENCE

INTRODUCTION TO CAUSALITY

“The questions that motivate most studies in the health, social and behavioral sciences are not associational but causal in nature. For example, what is the efficacy of a given drug in a given population? What was the cause of death of a given individual, in a specific incident? These are causal questions because they require some knowledge of the data-generating process; they cannot be computed from the data alone, nor from the distributions that govern the data” (@Pearl2009).

"The aim of standard statistical analysis is to assess parameters of a distribution from samples drawn of that distribution. With the help of such parameters, associations among variables can be inferred, which permits the researcher to estimate probabilities of past and future events and update those probabilities in light of new information. These tasks are managed well by standard statistical analysis so long as experimental conditions remain the same. Causal analysis goes one step further; its aim is to infer probabilities under conditions that are changing, for example, changes induced by treatments or external interventions.

This distinction implies that causal and associational concepts do not mix; there is nothing in a distribution function to tell us how that distribution would differ if external conditions were to change—say from observational to experimental setup—because the laws of probability theory do not dictate how one property of a distribution ought to change when another property is modified. This information must be provided by causal assumptions which identify relationships that remain invariant when external conditions change.

Causal relations cannot be expressed in the language of probability and, hence, that any mathematical approach to causal analysis must acquire new notation – probability calculus is insufficient. To illustrate, the syntax of probability calculus does not permit us to express the simple fact that “symptoms do not cause diseases,” let alone draw mathematical conclusions from such facts. All we can say is that two events are dependent—meaning that if we find one, we can expect to encounter the other, but we cannot distinguish statistical dependence, quantified by the conditional probability P(disease|symptom) from causal dependence, for which we have no expression in standard probability calculus." (Pearl 2010)

Summary: The difference between association and causality is that causality is directional, which cannot be represented with standard calculus notation.

CAUSATION

types of associations

A statistical association between an exposure and an outcome can be due to either or both a:

  • causal effect: the exposure causes the outcome. This is the effect we want to isolate using causal inference.

  • spurious effect: the exposed and the unexposed groups in the study are not comparable, or exchangeable, which is the ultimate source of the bias (the unexposed group is not the counterfactual of the exposed group) (@Hernan2002).

  • a common effect = collider

types of causal relationships

necessary

disease does not develop without this factor

sufficient

disease always develops with this factor

  1. necessary AND sufficient: without that factor, the disease never develops, and in the presence of that factor, the disease always develops. This never occurs in nature, even pathogens require other factors.

  2. necessary AND NOT sufficient: each factor is needed but alone is not able to cause disease. Ex: pathogen + immune susceptibility

  3. NOT necessary BUT sufficient: each factor alone is able to cause disease, but so can other factors. Ex: leukemia can be caused by radiation or benzene exposure

  4. NOT necessary NOR sufficient: presence of the factor by itself does not cuase disease

Gordis figure 14-12 to 14-15

direct effect

Example: a direct effect would arise because younger people change faster than older people and are therefore more likely to grow incompatible with a partner.

indirect effect

Example: age of marriage has an indirect effect by influencing the marriage rate, which then influences divorce. If people get married earlier, then the marriage rate may rise, because there are more young people. Consider for example if an evil dictator forced everyone to marry at age 65. Since a smaller fraction of the population lives to 65 than to 25, forcing delayed marriage will also reduce the marriage rate. If marriage rate itself has any direct effect on divorce, maybe by making marriage more or less normative, then some of that direct effect could be the indirect effect of age at marriage.

guidelines for establishing a causal relationship

Koch-Henle Criteria

  1. The organism is always found with the disease

  2. The organism is not found with any other disease

  3. The organism isolated from one individual with disease produces the disease in other individuals

Bradford Hill Criteria

Most important

  1. temporal relationship: exposure to the factor occurs before disease

  2. biologic plausibility: the association makes sense in the contex of existing knowledge.

  3. consistency: the same result is replicated in different studies and populations

  4. alternative explanations: confounding. exploration of the effect of other factors on the association.

Others

  1. strength: as measured by measures of effect (risk ratio or odds ratio)

  2. dose - response: the higher the exposure, the higher the risk of disease

  3. specificity: hard to ascertain as most outcomes are multifactorial

  4. cessation effect: if the exposure ceases, so does the effect

MEASURES OF DISEASE EFFECT OR ASSOCIATION

Measures of effect compare an exposed population to it’s counterfactual unexposed population, that is the exact same population at the same time point had it not been exposed. That is, the effect of \(E^+\) on the probability of being \(D^+\) in the SAME population.

Measures of association compare one exposed population to another unexposed population (a different population or the same population at a different time point) assuming that both populations are comparable. That is the effect of \(E^+\) on the probability of being \(D^+\) between \(E^-\) and \(E^+\).

causal types

Doomed = always has disease, exposed or not

Susceptible = has disease when exposed

Protected= does not have disease when exposed, but has disease when unexposed

Immune= never has disease, exposed or not

\(P(D^+|E^+) = p_1 + p_2 = doomed + susceptible\)

\(P(D^-|E^+) = p_3 + p_4 = protected + immune\)

\(P(D^+|E^-) = p_1 + p_3 = doomed + protected\)

\(P(D^-|E^-) = p_2 + p_4 = susceptible + immune\)

Disease + Disease - Total
Exposed + a = E(+) & D(+) b = E(+) & D(-) a+b = E(+)
Exposed - c = E(-) & D(+) d = E(-) & D(-) c+d = E(-)
Total a+c = D(+) b+d = D(-) a+b+c+d = total

measures of disease effect or association

Conditional probability refresher = \(P(A|B)=\frac{P(A \cup B)}{P(B)}\)

absolute risk = incidence

Measures magnitude of risk. Does not take into account the unexposed population or whether risk is associated to exposure. \[P(D^+|E^+)=\frac{a}{a+b}=\frac{new\:cases\:observed\:over\:period\:t}{total\:population\:at\:risk\:during\:period\:t}\]

relative risk = risk ratio

Measures the strength of the association and possible causal relationship

RR = 1 \(\to\) no effect

\[\frac{P(D^+|E^+)}{P(D^+|E^-)}=\frac{\frac{a}{a+b}}{\frac{c}{c+d}}=\frac{incidence\:in\:exposed\:population}{incidence\:in\:unexposed\:population}\] It can be expressed as:

  • Risk Ratio = RR = the ratio of cumulative incidence in the exposed and unexposed populations

\[\frac{P(D^+|E^+)}{P(D^+|E^-)}=\frac{\frac{a}{a+b}}{\frac{c}{c+d}}=\frac{D^+\:in\:exposed\:population}{D^-\:in\:unexposed\:population}\]

  • Incidence Rate Ratio = IRR or IDR = the ratio of incidence densities in the exposed and unexposed populations

\[\frac{D^+\:in\:person-time\:of\:exposed\:population}{D^+\:in\:person-time\:of\:unexposed\:population}=\frac{incidence\:in\:exposed\:population}{incidence\:in\:unexposed\:population}\]

odds ratio

Measures the strength of the association but cannot suggest a causal relationship

\[\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}=\frac{\frac{a}{b}}{\frac{c}{d}}=\frac{ad}{bc}=\frac{odds\:D^+\:in\:exposed\:population}{odds\:D^+\:in\:unexposed\:population}\] or

\[\frac{\frac{P(E^+|D^+)}{P(E^-|D^+)}}{\frac{P(E^+|D^-)}{P(E^-|D^-)}}=\frac{\frac{a}{c}}{\frac{b}{d}}=\frac{ad}{bc}=\frac{odds\:E^+\:in\:diseased\:population}{odds\:E^+\:in\:not\:diseased\:population}\]

A: cohort study, B: case-control study, Gordis Figure 11-5

matched-pairs OR:

Gordis Figure 11-9

ODDS RATIO CAN BE A GOOD ESTIMATE OF RELATIVE RISK When:

\[\frac{P(D^+|E^+)}{P(D^+|E^-)}\approx\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}\] \[\frac{\frac{a}{a+b}}{\frac{c}{c+d}} \approx \frac{\frac{a}{b}}{\frac{c}{d}}\]

  • We assume the disease is rare:
    • rare disease assumption

When the disease does not occur frequently \(a+b \approx b\) and \(c+d \approx d\)

Gordis Figure 11-6, 11-7

  • The cases are representative, with regards to the history of exposure, of all the people with disease in the population from which the cases were drawn:

  • The controls are representative, with regards to the history of exposure, of all the people without disease in the population from which the cases were drawn:

The controls can be selected through different methods:

  • Not matched on time

    • case-based sampling: sampling occurs at the beginning of the study (\(t_0\))

    • cumulative incidence sampling: sampling occurs at the end of the study (\(t_1\))

assumption of constant incidence density rate over the period of time: \(\frac{ID_{exposed(t)}}{ID_{unexposed(t)}}=\bar{IDR}_{t_0 \to t_1}\)

assumption of a stable population with respect to exposure = time is NOT a confounder

  • Matched on time

    • incidence density sampling: match on time with the cases (\(t_0 - t_1\))

assumption of constant incidence density rate over the period of time: \(\frac{ID_{exposed(t)}}{ID_{unexposed(t)}}=\bar{IDR}_{t_0 \to t_1} \to ID_{exposed(t)} = ID_{unexposed(t)} * \bar{IDR}_{t_0 \to t_1}\)

Both incidence and exposure change in function of time, therefore time is a confounder. By selecting the controls matching on time, we can interpret the odds ratio as a rate or risk measure, without making the rare disease assumption, by assuming only that the incidence is constant over time.

INTERPRETATION OF ODDS RATIO

\[\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}= \frac{\frac{a/a+b}{b/a+b}}{\frac{c/c+d}{d/c+d}} \ne \frac{\frac{a}{b}}{a+b}\]

Ratio of average risk \(\frac{P(D^+|E^+)}{P(D^-|E^+)}= \frac{a/a+b}{b/a+b}\) to average survival probability \(\frac{P(D^+|E^-)}{P(D^-|E^-)}= \frac{c/c+d}{d/c+d}\)

which is not the same as the average disease odds \(\frac{a/b}{a+b}\)

attributable risk

Incidence of a disease in the exposed population that is attributable to the exposure.

If > 1 the risk in the presence of exposure is greater that not in the presence of exposure

How much of the disease would be prevented if the exposure were eliminated?

\[{P(D^+|E^+)}-{P(D^+|E^-)}={\frac{a}{a+b}}-{\frac{c}{c+d}}={incidence\:in\:exposed\:population} -{incidence\:in\:unexposed\:population}\]

as a proportion:

\[\frac{{P(D^+|E^+)}-{P(D^+|E^-)}}{P(D^+|E^+)}=\frac{{\frac{a}{a+b}}-{\frac{c}{c+d}}}{\frac{a}{a+b}}=\frac{{incidence\:in\:exposed\:population} -{incidence\:in\:unexposed\:population}}{incidence\:in\:exposed\:population}\] \[\frac{{P(D^+|E^+)}/{P(D^+|E^-)}-{P(D^+|E^-)}/{P(D^+|E^-)}}{P(D^+|E^+){P(D^+|E^-)}}= \frac{RR - 1}{RR}= 1- 1/RR\]

Grodis figure 12-1 Gordis Table 12.1

ATTRIBUTABLE FRACTIONS

  • Etiologic fraction: proportion of cases in exposed population where exposure has a biological role in the disease

  • Excess fraction: proportion of cases in exposed population where exposure has a role of incrementing the disease incidence vs the unexposed population

population attributable risk

Incidence of a disease in the total population that is attributable to the exposure.

How much of the disease in the total population would be prevented if the exposure were eliminated?

Incidence in the total population: \(P(D^+|E^+) * P(E^+) + P(D^+|E^-) * P(E^-)= \frac{a}{a+b} * \frac{a+b}{a+b+c+d} + \frac{a}{c+d} * \frac{c+d}{a+b+c+d}= incidence\:in\:exposed\:population * proportion\:exposed\:population + incidence\:in\:unexposed\:population * proportion\:unexposed\:population\)

\[\frac{[P(D^+|E^+) * P(E^+) + P(D^+|E^-) * P(E^-)]-{P(D^+|E^-)}}{P(D^+|E^+) * P(E^+) + P(D^+|E^-) * P(E^-)}=\frac{[{\frac{a}{a+b} * \frac{a+b}{a+b+c+d} + \frac{a}{c+d} * \frac{c+d}{a+b+c+d}}]-{\frac{c}{c+d}}}{\frac{a}{a+b} * \frac{a+b}{a+b+c+d} + \frac{a}{c+d} * \frac{c+d}{a+b+c+d}}=\frac{{incidence\:in\:total\:population} -{incidence\:in\:unexposed\:population}}{incidence\:in\:total\:population}\]

Gordis formula 12-4

ERROR IN INFERENCE

  • random error

Chance or random variation that remains unexplained.

The association lacks precision. The results are less reproducible.

  • systematic error = bias

The association lacks validity. The results are biased.

insert irva/Causal Inference: What If by Miguel A. Hernán, James M. Robins here

MEASURES OF ACCURACY

precision/reliability

the amount of random error. High precision indicates the results are always similar in different experiments.

validity

the amount of systematic error. High validity indicates proximity to the true value

  • external validity: generalizability of the results to the general population

  • internal validity: comparability among the groups in the study

Gordis figure 15-9

RANDOM ERROR

  • unexplained variation : non-deterministic counterfactuals

  • sampling error : the degree to which a sample population deviates from the total population. It’s unpredictable and due to the sampling process.

A sample is

a subset of the subjects in the population that could have been included in the study = a subset of the experiences the study subjects could have had

STATISTICAL INFERENCE

approaches to deal with random error

ASSUMPTIONS OF SAMPLING

  • Randomness assumption: the sample is a random selection of the subjects in the population that could have been included in the study

  • Representativeness assumption: the sample is representative of the subjects in the population that could have been included in the study

SAMPLING DISTRIBUTION

Different samples result in different measures of occurrence.

Sample size will determine:

  • the magnitude of the effect = the proximity of the measure of occurrence to the true value

  • the precision of the estimation method = statistical precision: the inverse of the variance.

hypothesis testing

interpretation of the hypothesis test:

\(H_0\): hypothesis that there is no association between 2 variables in the superpopulation that was sampled.

  • Reject the \(H_0\): Under the sampling distribution of the \(H_0\), the observed point estimate of the sample is inconsistent with the \(H_0\) for a given critical threshold (\(\alpha\) = 0.05).

  • Fail to reject the \(H_0\): Under the sampling distribution of the \(H_0\), the observed point estimate of the sample is consistent with the \(H_0\) for a given critical threshold (\(\alpha\) = 0.05). We cannot reject the \(H_0\) that the superpopulation groups are the same.

MISinterpretation of the hypothesis test:

  • Reject the \(H_0\): the superpopulation groups are the different.

There could be sources of uncontrolled bias, or chance alone could haveled to this point estimate.

  • Fail to reject the the \(H_0\): the 2 observed groups from the superpopulation are the same.

Hogg,Tannis,Zimmerman Hogg,Tannis,Zimmerman

significance testing

interpretation of the significance test:

p-value: probability of observing a more extreme point estimate than that observed in the sample if the \(H_0\) were true.

Reject the \(H_0\): probability of observing a more extreme point estimate than that observed in the sample if the \(H_0\) were true is less than the probability of the critical region (\(\alpha\) = 0.05) = the smallest critical region (\(\alpha\)) that would lead us to reject the \(H_0\) if it were true.

MISinterpretation of the significance test:

  • p-value: probability of the observed data under the test hypothesis Incorrect because the p-value includes all other configurations of the data that result in a more extreme test statistic than that observed in the sample.

  • p-value: probability of the observed data would show as strong an association or stronger under the test hypothesis

Hogg,Tannis,Zimmerman

STATISTICAL ESTIMATION

Epidemiological analysis is a measurement, not a decision-making, problem. We want to estimate

  • the magnitude of the effect = point estimate. The proximity of the measure of occurrence to the true value depends on sample size, bias, random error, etc…

  • the precision of the estimation method = statistical precision: the inverse of the variance. Uncertainty of the point estimate. It depends on the random variability, the sample size, etc…

Interval estimation: provides information on:

  • the direction and magnitude of the association
  • the random variability in the point estimate.

significance testing reduce the information to a yes/no choice. It provides the degree of consistency between the data and a single hypothesis.

SYSTEMATIC ERROR = BIAS

SELECTION BIAS

Non-comparability of the exposed and unexposed groups induced by a restriction in the analysis on certain level/s of a common effect of E or O or variables correlated with E or O.

This can be caused by:

  • unbalanced sampling fractions between the exposed and non-exposed population (see example below).

  • over-matching: when the cases and controls are matched on a factor that is not associated with the outcome but is associated with exposure.

The difference with confounding: confounding is due to unmeasured common causes and selection bias is due to errors in the selection of the two study groups that affects the internal validity.

  • non-response bias: survey non-respondents may have different characteristics than those who do respond

  • exclusion bias: different eligibility criteria between cases and controls or the controls are selected from a different population than the cases Foor example, if the disease is very deadly and the information about the cases comes from proxies (relatives, friends) that are from a different population than the controls.

    • berkson’s bias: “If the only way to cross the threshold is to score high, it is more common to score high on one item than on both. This general phenomenon is sometimes called Berkson’s paradox . But it is easier to remember if we call it the selection-distortion effect. Why do so many restaurants in good locations have bad food? The only way a restaurant with less-than-good food can survive is if it is in a nice location. Similarly, restaurants with excellent food can survive even in bad locations. Selection-distortion ruins your city.”(@mcelreath). In case-control studies that select cases from hospitals, often these cases are more likely to have concomitant diseases (hypertension, obesity) than the general population, which can lead to spurious associations.

    • incidence/prevalence bias: Studies that select cases from hospitals are selecting for severe disease and having survived longer. To avoid this bias it’s better to select incidence cases.

Selection bias does not depend only on exposure, it depends on the sampling fraction of all the cells, that means it can also depend on disease.

INFORMATION BIAS

Bias caused by measurement errors. Individuals are categorized incorrectly.

For continuous variables = INFORMATION ERROR

For categorical variables = MISCLASSIFICATION

  • DIFFERENTIAL: the classification error depends on the actual values of other variables, that is, it varies between the study groups. The bias can be either towards or away from the \(H_0\).

    • recall bias: memory of events may bary between cases and controls. Example: Outcome: congenital malformation; Exposure: any; mothers of cases may have a better memory of the exposure than mothers of controls.

    • detection/surveillance bias: the diagnosis of the outcome may be earlier or better in monitored study groups than in the general population. Example: Outcome: emphysema; Exposure: smoking; smokers have more respoiratory issues and seek out medical care more often, therefore emphysema is detected earlier and more often in the exposed than in the unexposed.

    • observer bias: there is a systematic difference in how data are collected between study participants belonging to different groups. Occurs when the interviewer is not blinded and when there is interviewer drift, that is, when the data collection procedure for the same interviewer changes over time.

  • NON-DIFFERENTIAL: the classification error dos NOT depend on the actual values of other variables, and is due to a lack of accuracy in the data collection. This bias is usually towards the \(H_0\), diluting the magnitude of effect (RR and OR), but it can be away from the \(H_0\) if the exposure or outcome variables are non-binary, or if it’s a dependent missclasification (depends on error in the classification of other variables).

    • observer bias: Example: surrogate interviews, where the information might be inaccurate.

    NON-DIFFERENTIAL EXPOSURE MISSCLASIFICATION

    Modern Epidemiology

    NON-DIFFERENTIAL DISEASE MISSCLASIFICATION

    Modern Epidemiology

  • DEPENDENT: the classification error depends on errors made measuring or classifying other variables.

  • INDEPENDENT: the classification error does NOT depend on errors made measuring or classifying other variables.

CONFOUNDING

The exposed and the unexposed in the study are not comparable, or exchangeable, which is the ultimate source of the bias ( the unexposed group is not the counterfactual of the exposed group)

A CONFOUNDER is a variable that is:

  • associated with the outcome, conditional on the exposure (i.e. in the exposed group) Example: smoking is a risk factor for cancer

  • associated with the exposure, conditional on the exposure (i.e. in the exposed group) Example: smoking is associated with drinking coffee

  • not on the causal pathway between the exposure and the outcome. Example: smoking is not a result of drinking coffee

difference between confouding and selection bias

  • There is confounding when the association between exposure and outcome includes a noncausal component attributable to their having an uncontrolled common cause.

  • There is selection bias when the association between exposure and outcome includes a noncausal component attributable to restricting the analysis to certain level(s) of a common effect of exposure and outcome or, more generally, to conditioning on a common effect of variables correlated with exposure and outcome.

methods for identifying/detecting confounding

The following methods are extracted from @Hernan2002

Statistical criteria alone are insufficient to characterize either confounding or selection bias. The only method to reliably identify a counfounder is to combine statistical associations from the data with background knowledge about the causal network that links exposure, outcome, and potential confounders.

  • Methods relying on statistical associations that can easily be identified from the data:

  1. automatic variable selection procedures: i.e stepwise regression. It’s based on including variables with “significant” p-values. It assumes that all important confounders will be selected.

  2. change in effect estimate: comparison of the effect estimates between adjusted and unadjusted effect estimates. It assumes that any variable substantially associated with an estimate change is worth adjusting for.

We evaluate the effect measure of the exposure of interest: crude and stratified by the possible confounder. If the stratum-specific effect measures are similar to each other but different to the crude effect measure and the relative change greater than 10%, the variable is selected as a confounder. This change can be evaluated on the probability scale or transformed scale (exampe \(\beta\) coefficient or OR for the exposure in a logistic model)

Example: Is the association causal or confounded by age?

  • Methods that combine statistical associations from the data with background knowledge:
  1. check whether the variable meets the criteria of a confounder: combines information from statistical associations and background knowledge. The presence of common causes, and therefore of confounding, can be represented by causal diagrams known as directed acyclic graphs (DAGs).

DAG = Directed Acyclic Graph

DAGs are diagrams that link variables by arrows that represent direct causal effects (protective or causative) of one variable on another.

There are only four types of variable relations that combine to form all possible paths (from @mcelreath2020):

  1. the confounder = fork: X ← Z → Y. This is the classic confounder: some variable Z is a common cause of X and Y, generating a correlation between them. If we condition on Z, then learning X tells us nothing about Y. X and Y are independent, conditional on Z.

  2. the pipe = intermediary: X → Z → Y. The treatment X influences Z which influences Y. If we condition on Z, we block the path from X to Y. X and Y are independent, conditional on Z.

  3. the collider = common effect: X → Z ← Y. Conditioning on Z, the collider variable, opens the path. X and Y are dependent, conditional on Z, however neither X nor Y has any causal influence on the other.

  4. the descendent = association?: Z \(\to\) D. Descendent is a variable influenced by another variable. Conditioning on a descendent partly conditions on its parent. Conditioning on D will also condition, to a lesser extent, on Z because D has some information about Z.

Backdoor criterion

Path: any series of variables you could walk through to get from one variable to another, ignoring the directions of the arrows.

Blocking all confounding paths between some predictor X and some outcome Y is known as shutting the backdoor, thus eliminating spurious associations that are non-causal.

Example:

There are two paths connecting E and O:

  1. E → O

  2. E ← C → O.

Both of these paths create a statistical association between E and O. But only the first path is causal. The second path is non-causal. If only the second path existed, and we changed E, it would not change O. Any causal influence of E on O operates only on the first path.

REMINDER:

  • causal effect: The total causal effect is the sum of the direct and indirect effects: Example: age of marriage influences divorce in two ways.

    • direct effect. A \(\to\) D Example: a direct effect would arise because younger people change faster than older people and are therefore more likely to grow incompatible with a partner.

    • indirect effect. A \(\to\) M \(\to\) D Example: age of marriage has an indirect effect by influencing the marriage rate, which then influences divorce. If people get married earlier, then the marriage rate may rise, because there are more young people. Consider for example if an evil dictator forced everyone to marry at age 65. Since a smaller fraction of the population lives to 65 than to 25, forcing delayed marriage will also reduce the marriage rate. If marriage rate itself has any direct effect on divorce, maybe by making marriage more or less normative, then some of that direct effect could be the indirect effect of age at marriage.

  • spurious effect

Do-operator

do(E) closes the backdoor paths into E, as in a manipulative experiment.

P(O|do(E)) defines a causal relationship because it tells us the expected result of manipulating E on O

  • Confounding: P(O|E) \(\ne\) P(O|do(E)). The relationship between the E and O when the backdoor paths are closed is not the same, indicating that there is confounding.

  • Conditional probability, non-causal: P(O|E) \(\ne\) P(O|not-E) doesn’t close the backdoor, and therefore does not give a causal relationship.

  • Total causal relationship: if P(O|do(E)) \(\ne\) P(O|not-E), then E is the cause of O.

  • Direct causal relationship: might require closing more backdoor paths.

Examples from @Hernan2002

Example using all 3 methods of identifying confounders:

Steps to identify which variables are confounders and must be controlled to obtain and unbiased causal effect estimate:

  1. List all of the paths connecting E (the potential cause of interest) and O (the outcome).

  2. Classify each path by whether it is open or closed. A path is open unless it contains a collider.

  3. Classify each path by whether it is a backdoor path. A backdoor path has an arrow entering E.

  4. If there are any open backdoor paths, decide which variable(s) to condition on to close it (if possible). To obtain a sufficient set, use the smallest set of confounders (preferable closer to the outcome)

  • Obtaining an unbiased estimate of the total causal effect requires measuring and adjusting for all confounders of the E \(\to\) O association

  • Obtaining an unbiased estimate of the direct causal effect requires measuring and adjusting for all confounders of both the

    • E \(\to\) O association

    • J \(\to\) O association

  1. Example 1

  • To obtain the total causal effect we don’t condition on C or J:

    • C is a confounder of the J \(\to\) O association but not the E \(\to\) O association, thanks to J which is a collider and blocks the path between C \(\to\) E, so it is unnecessary to control for C

  • J is a collider of the E \(\to\) C association so if we condition on J we create a backdoor path between O \(\to\) E through C.

  • To obtain the direct causal effect we condition on both J and C, because we want only the

  1. Example 2

  • To obtain the total causal effect we condition on C but not J:

    • C is a confounder of the E \(\to\) O association so we must condition on it to obtain the unbiased total causal effect

  • To obtain the direct causal effect we condition on J. C is no longer a confounder because we block the path through J so it’s no longer associated with O.

  1. Example 3.

  • To obtain the total causal effect we condition on D

  • To obtain the total causal effect we condition on C, D, J

TESTABLE IMPLICATIONS

Testable implications can be read off the diagrams using a graphical criterion known as d- separation (Pearl, 1988). Each diagram encodes causal assumptions, each corresponding to a missing arrow or a missing double-arrow between a pair of variables.

DAGs imply that some variables are independent of others under certain conditions, therefore the testable implications of a DAG are it’s CONDITIONAL INDEPENDENCIES.

CONDITIONAL INDEPENDENCIES describe which variables should be associated with one another (or not) in the data, and which variables become disassociated when we condition on some other set of variables.

Condition independencies are pairs of variables that are not associated, once we condition on some set of other variables.

Conditioning: conditioning on a variable Z means learning its value and then asking if X adds any additional information about Y. If learning X doesn’t give you any more information about Y, then we might say that Y is independent of X conditional on Z. This conditioning statement is sometimes written as: \(Y \!\perp\!\!\!\perp X|Z\)

\(X \not\!\perp\!\!\!\perp Y\) means “not independent of”

\(X \!\perp\!\!\!\perp Y\) means “independent of”

Marginal and conditional assotiation

Modern Epidemiology

methods for controlling confounding = obtaining an unbiased estimate of the causal effect

DURING STUDY DESIGN

Manipulation of the confounding factor in the study design removes the influence of C on E: when we determine E, the C variable does not influence E, thus blocking the non-causal path between E and O (E ← C → O). Once the path is blocked, there is only one way for information to go between E and O, and then measuring the association between E and O would yield a useful measure of causal influence.

  • Randomization: limits confounding by unmeasured factors probabilistically and accounts quantitavely for any residual confounding they produce.

Limitations: feasibility, ethics

  • Restriction: the individuals in the study may be selected to have equal levels of the confounder.

Limitations: reduction of the number of available individuals, the factor that is used for restriction can’t be analyzed, possible residual confounding if the restriction is insufficient.

  • Matching: it does not control for confounding, but it increases the efficiency of the study that does control for confounding, as the confounding factor may still be controlled in the analysis.

Limitations: expensive, complicated logistics, the factor that is used for matching can’t be analyzed, as the variables must be collected before participant enrollment

DURING DATA ANALYSIS

Conditioning on the confounding factor in the study analysis: adding C to the model blocks the non-causal path E ← C → O.

Why? Think of this path in isolation, as a complete model.

Once you learn C, also learning E will give you no additional information about O.

Example: Suppose for example that C is the average wealth in a region. Regions with high wealth have better schools, resulting in more education (exposure E), as well as better paying jobs, resulting in higher wages (outcome O). If you don’t know the region a person lives in, learning the person’s education E will provide information about their wages O, because E and O are correlated across regions. But after you learn which region a person lives in, assuming there is no other path between E and O, then learning E tells you nothing more about O. This is the sense in which conditioning on C blocks the path — it makes E and O independent, conditional on C.

  • multivariate adjustment: using regression, ANOVA, etc.. It can handle multiple covariates at the same time.

Limitations: unless background knowledge is included in the variable selection, confounding can persist.

  • stratification: the data is stratified by a confounder and the weighted averages of the effect measure (RR or OR) across strata is calculated and then compared to the crude estimate and to each other using the Cochran-Maentel-Haenszel estimate. \(OR_{EO}\) vs \(OR_{EO|C}\)

Limitations: can only be performed for few variables at a time

  • standarization: re-weight the stratum-specific effect measures (RR, OR) so that the categories are comparable using a reference population from the data set r an external source.

Limitations: can only be performed for few variables at a time

  • inverse probability treatment: creates a pseudo-population without confounding by re-weighting, yet the true exposure is not altered. It can be used for time-dependent confounding, when earlier exposure can influence later exposure.

Modern Epidemiology

confounding example from @mcelreath2020

We look into causal inference using a working example from Statistical Rethinking: A Bayesian Course with Examples in R and Stan. Second edition by Richard McElreath: Correlation between marriage rate (the exposure) and divorce rate (the outcome).

# load data and copy 
library(rethinking) 
data(WaffleDivorce) 
d <- WaffleDivorce
# standardize variables
d$D <- standardize( d$Divorce )
d$M <- standardize( d$Marriage )
d$A <- standardize( d$MedianAgeMarriage )

EXAMPLE 1

There are three observed variables in play: divorce rate (D), marriage rate (M), and the median age at marriage (A) in each State of the U.S. Both marriage rates and median age at marriage are great predictors of the divorce rate in a given State, but are these relationships causal?

The rate at which adults marry (M) is a great predictor of divorce rate. But does marriage cause divorce? In a trivial sense it obviously does: One cannot get a divorce without first getting married. But there’s no reason high marriage rate must cause more divorce. It’s easy to imagine high marriage rate indicating high cultural valuation of marriage and therefore being associated with low divorce rate.

Age at marriage (A) is also a good predictor of divorce rate— higher age at marriage predicts less divorce. But there is no reason this has to be causal, either, unless age at marriage is very late and the spouses do not live long enough to get a divorce.

Age of marriage influences divorce in two ways:

  • direct effect: a direct effect would arise because younger people change faster than older people and are therefore more likely to grow incompatible with a partner.

  • indirect effect: age of marriage has an indirect effect by influencing the marriage rate, which then influences divorce. If people get married earlier, then the marriage rate may rise, because there are more young people. Consider for example if an evil dictator forced everyone to marry at age 65. Since a smaller fraction of the population lives to 65 than to 25, forcing delayed marriage will also reduce the marriage rate. If marriage rate itself has any direct effect on divorce, maybe by making marriage more or less normative, then some of that direct effect could be the indirect effect of age at marriage.

To infer the strength of these different arrows, we need more than one statistical model.

To obtain the total effect of of age at marriage on divorce rate we condition on age at marriage.

The total causal effect is the sum of the direct and indirect effects

We assume that these variables are associated. If we look in the data and find that any pair of variables are not associated, then something is wrong with the DAG (assuming the data are correct). In these data, all three pairs are in fact strongly associated. We can use cor to measure simple correlations. Correlations are sometimes terrible measures of association—many different patterns of association with different implications can produce the same correlation. But they do honest work in this case.

cor(d$D, d$M)
## [1] 0.3737314
cor(d$D, d$A)
## [1] -0.5972392
cor(d$M, d$A)
## [1] -0.721096
  • Model conditioning on A

\(D_{i} ∼ Normal(\mu_{i}, \sigma)\)

\(\mu_{i} = \alpha + \beta_{A}A_{i}\)

m5.1 <- quap(
    alist(
        D ~ dnorm( mu , sigma ) ,
        mu <- a + bA * A ,
        a ~ dnorm( 0 , 0.2 ) ,
        #when βA = 1, a change of 1.2 years in median age at marriage is associated with a full standard deviation change in the outcome variable (divorce)
        #only 5% of plausible slopes more extreme than 1.
        bA ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
) , data = d )

precis(m5.1)
##                mean         sd       5.5%      94.5%
## a     -1.016764e-05 0.09737649 -0.1556366  0.1556163
## bA    -5.684060e-01 0.10999656 -0.7442017 -0.3926102
## sigma  7.883015e-01 0.07800537  0.6636338  0.9129691

The outcome and the predictor are both standardized, the intercept α should end up very close to zero.

What does the prior slope \(\beta_{A}\) imply? If \(\beta_{A}\) = 1, that would imply that a change of one standard deviation in age at marriage is associated likewise with a change of one standard deviation in divorce. To know whether or not that is a strong relationship, you need to know how big a standard deviation of age at marriage is:

 sd( d$MedianAgeMarriage )
## [1] 1.24363

So when \(\beta_{A}\) = 1, a change of 1.2 years in median age at marriage is associated with a full standard deviation change in the outcome variable. That seems like an insanely strong relationship.

posterior for \(\beta_{A}\) is reliably negative, as seen:

# compute percentile interval of mean
A_seq <- seq( from=-3 , to=3.2 , length.out=30 )
mu <- link( m5.1 , data=list(A=A_seq) )
mu.mean <- apply( mu , 2, mean )
mu.PI <- apply( mu , 2 , PI )
# plot it all
plot( D ~ A , data=d , col=rangi2 )
lines( A_seq , mu.mean , lwd=2 )
shade( mu.PI , A_seq )

Model m5.1, the regression of D on A, tells us only that the total influence of age at marriage is strongly negative with divorce rate. The “total” here means we have to account for every path from A to D. There are two such paths in this graph: A → D, a direct path,and A → M → D, an indirect path.

In general, it is possible that a variable like A has no direct effect at all on an outcome like D. It could still be associated with D entirely through the indirect path. That type of relationship is known as mediation.

As you’ll see however, the indirect path does almost no work in this case. How can we show that?

  • Model conditioning on M

\(D_{i} ∼ Normal(\mu_{i}, \sigma)\)

\(\mu_{i} = \alpha + \beta_{M}M_{i}\)

m5.2 <- quap(
    alist(
        D ~ dnorm( mu , sigma ) ,
        mu <- a + bM * M ,
        a ~ dnorm( 0 , 0.2 ) ,
        bM ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
) , data = d )

precis(m5.2)
##               mean         sd       5.5%     94.5%
## a     4.620717e-07 0.10824653 -0.1729984 0.1729993
## bM    3.500471e-01 0.12592766  0.1487903 0.5513038
## sigma 9.102667e-01 0.08986274  0.7666487 1.0538847
# compute percentile interval of mean
M_seq <- seq( from=-3 , to=3.2 , length.out=30 )
mu <- link( m5.2 , data=list(M=M_seq) )
mu.mean <- apply( mu , 2, mean )
mu.PI <- apply( mu , 2 , PI )
# plot it all
plot( D ~ M , data=d , col=rangi2 )
lines( M_seq , mu.mean , lwd=2 )
shade( mu.PI , M_seq )

This relationship isn’t as strong as the one between A and D.

The pattern we see in the previous two models is symptomatic of a situation in which only one of the predictor variables, A in this case, has a causal impact on the outcome, D, even though both predictor variables are strongly associated with the outcome.

We know from the model conditioning on M (m5.2) that marriage rate is positively associated with divorce rate. But that isn’t enough to tell us that the path M → D is positive. It could be that the association between M and D arises entirely from A’s influence on both M and D. Like this:

This DAG is also consistent with the posterior distributions of models m5.1 and m5.2. Why? Because both M and D “listen” to A. They have information from A. So when you inspect the association between D and M, you pick up that common information that they both got from listening to A.

So which is it? Is there a direct effect of marriage rate, or rather is age at marriage just driving both, creating a spurious correlation between marriage rate and divorce rate? To find out, we need to consider carefully what each DAG implies.

  1. M has influence on D

This DAG says:

  1. A directly influences D
  2. M directly influences D
  3. A directly influences M

There are 3 causal assumptions that can be tested (one for every arrow).

Before we condition on anything, we assume everything is associated with everything else.

The testable implications are:

  1. \(D \not\!\perp\!\!\!\perp A\) A not independent of D
  2. \(D \not\!\perp\!\!\!\perp M\) M not independent of D
  3. \(A \not\!\perp\!\!\!\perp M\) D not independent of A

implied conditional independencies = none

DMA_dag1 <- dagitty('dag{ D <- A -> M -> D }')

impliedConditionalIndependencies( DMA_dag1  )
  1. M has no influence on D

In this DAG, it is still true that all three variable are associated with one another. A is associated with D and M because it influences them both. And D and M are associated with one another, because A influences them both. They share a cause, and this leads them to be correlated with one another through that cause.

There are 2 causal assumptions that can be tested (one for every arrow).

  1. A causes D

(2) M causes D

  1. A causes M

But suppose we condition on A. All of the information in M that is relevant to predicting D is in A. So once we’ve conditioned on A, M tells us nothing more about D. So in the second DAG, a testable implication is that D is independent of M, conditional on A. In other words, \(D \!\perp\!\!\!\perp M|A\)

The testable implications are:

All 3 variables should be associated, before conditioning on anything:

  1. \(D \not\!\perp\!\!\!\perp A\) A not independent of D

  2. \(D \not\!\perp\!\!\!\perp M\) M not independent of D

  3. \(A \not\!\perp\!\!\!\perp M\) D not independent of A

  4. \(D \!\perp\!\!\!\perp M|A\) D and M should be independent after conditioning on A.

implied conditional independencies = D || M | A

DMA_dag2 <- dagitty('dag{ D <- A -> M }') 
impliedConditionalIndependencies( DMA_dag2  )
## D _||_ M | A

Test the difference between the two DAGs

The only implication that differs between these DAGs is the last one:\(D \!\perp\!\!\!\perp M|A\) D and M should be independent after conditioning on A.

To test this implication, we need a statistical model that conditions on A, so we can see whether that renders D independent of M. And that is what multiple regression helps with. It can address a useful descriptive question: Is there any additional value in knowing a variable, once I already know all of the other predictor variables?

So for example once you fit a multiple regression to predict divorce using both marriage rate and age at marriage, the model addresses the questions: (1) After I already know marriage rate, what additional value is there in also knowing age at marriage? (2) After I already know age at marriage, what additional value is there in also knowing marriage rate?

The parameter estimates corresponding to each predictor are the (often opaque) answers to these questions. The questions above are descriptive, and the answers are also descriptive. It is only the derivation of the testable implications above that give these descriptive results a causal meaning. But that meaning is still dependent upon believing the DAG.

For each predictor, the parameter measures its conditional association with the outcome.

  • Model conditioning on A and M

\(D_{i} ∼ Normal(\mu_{i}, \sigma)\)

\(\mu_{i} = \alpha + \beta_{M}M_{i} + \beta_{A}A_{i}\)

m5.3 <- quap(
    alist(
        D ~ dnorm( mu , sigma ) ,
        mu <- a + bM*M + bA*A ,
        a ~ dnorm( 0 , 0.2 ) ,
        bM ~ dnorm( 0 , 0.5 ) ,
        bA ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
    ) , data = d )
precis( m5.3 )
##                mean         sd       5.5%      94.5%
## a      2.129865e-07 0.09707605 -0.1551461  0.1551465
## bM    -6.538159e-02 0.15077308 -0.3063461  0.1755829
## bA    -6.135154e-01 0.15098360 -0.8548164 -0.3722144
## sigma  7.851182e-01 0.07784344  0.6607093  0.9095270

The posterior mean for marriage rate, bM, is now close to zero, with plenty of probability of both sides of zero. The posterior mean for age at marriage, bA, is essentially unchanged. It will help to visualize the posterior distributions for all three models, focusing just on the slope parameters βA and βM:

plot(coeftab(m5.1,m5.2,m5.3), par=c("bA","bM"))

bA doesn’t move, only grows a bit more uncertain, while bM is only associated with divorce when age at marriage is missing from the model. You can interpret these distributions as saying: Once we know median age at marriage for a State, there is little or no additional predictive power in also knowing the rate of marriage in that State, which means \(D \!\perp\!\!\!\perp M|A\). D and M are independent after conditioning on A, which corresponds to the second DAG.

Note that this does not mean that there is no value in knowing marriage rate. Consistent with the earlier DAG, if you didn’t have access to age-at-marriage data, then you’d definitely find value in knowing the marriage rate. M is predictive but not causal. Assuming there are no other causal variables missing from the model, this implies there is no important direct causal path from marriage rate to divorce rate. The association between marriage rate and divorce rate is spurious, caused by the influence of age of marriage on both marriage rate and divorce rate.

EXAMPLE 2

We’re interested in the total causal effect of the number of Waffle Houses on divorce rate in each State. Presumably, the naive correlation between these two variables is spurious. What is the minimal adjustment set that will block backdoor paths from Waffle House to divorce?

Let’s make a graph:

## { A, M }
## { S }

We could control for either A and M or for S alone. This DAG is obviously not satisfactory—it assumes there are no unobserved confounds, which is very unlikely for this sort of data. But we can still learn something by analyzing it. While the data cannot tell us whether a graph is correct, it can sometimes suggest how a graph is wrong.

Inspecting implied conditional independencies, we can at least test some of the features of a graph.

 impliedConditionalIndependencies( dag6 )
## A _||_ W | S
## D _||_ S | A, M, W
## M _||_ W | S

  1. The median age of marriage should be independent of (||) Waffle Houses, conditioning on (|) a State being in the south.

  2. Divorce and being in the south should be independent when we simultaneously condition on all of median age of marriage, marriage rate, and Waffle Houses.

  3. Marriage rate and Waffle Houses should be independent, conditioning on being in the south.

INTERACTION and EFFECT MEASURE MODIFICATION

An interaction occurs when the measure of association between a risk factor and outcome depends on the level of another factor.

difference between interaction and confounding

confounding interaction
origin property of distribution in source popuation biologic, sociologic…
distribution of the 3d variable differs by exposure status can be statistically independent of exposure
does the 3d variable predic the outcome? yes not necessarily
stratum-specific measures similar across strata differ across strata
crude overall measure differ from stratum-specific measures falls between stratum-specific measures
summary adjusted measure makes sense not meaningful
testing cannot test can test
relationship to the other if a strong interaction exists, it makes no sense to discuss confounding both may occur

difference between interaction and effect measure modification

Interaction, effect modification and effect heterogeneity sometimes are used to mean the same thing.

Interaction Tables

  • Risk of disease
A no A yes
B no Rab RAb
B yes RaB RAB
  • INTERACTION: we are equally interested in the change in RR in the presence of A and B and the combination of A and B.

Relative Risk in Interaction

A no A yes
B no 1 RAb/Rab
B yes RaB/Rab RAB/Rab
  • EFFECT MODIFICATION: we are interested in the change in RR of one of the variables in the presence of the other variable. Example: how does B change on different levels of A?

To obtain the relative risk measure, we divide the risk measures in the presence of A by the referent within each level of B, thus we have 2 groups, one for each strata.

Relative Risk in effect modification

A no A yes
B no 1 RaB/Rab
B yes 1 RAB/RAb

types of interaction

  • synergism: the additive measure of joint exposure is MORE THAN the sum of the measures of association between exposure and outcome for each exposure alone.

  • antagonism: the additive measure of joint exposure is LESS THAN the sum of the measures of association between the exposure and outcome for each exposure alone.

types of interaction effect

  • additive: Excess risk and linear regression are on the additive scale.

  • multiplicative: Relative risk, logistic, Poisson and porportional hazards models all assume factors act multiplicatively unless an interaction effect is included.

Gordis

Example:

A logistic regression is on the additive scale when it’s transformed:

\(logit(\hat{p_i}) = log(p_i/(1-p_i)) = log(ODDS) =\beta_0 +\beta_A x_A + \beta_B x_B + +\beta_{AB} x_A x_B\)

But a logistic regression is on the multiplicative scale when it’s on the original probability scale:

\(p_i/(1-p_i) = ODDS =e^{\beta_0 +\beta_A x_A + \beta_B x_B + +\beta_{AB} x_A x_B}\)

Is A and effect modifier of B? What is the effect of B versus no B?

  • In the presence of A: \(x_A = 1\)

    • In the presence of B: \(x_B = 1\)

    \(log(ODDS) =\beta_0 +\beta_A x_A + \beta_B x_B + \beta_{AB} x_A x_B\)

    • Not in the presence of B: \(x_B = 0\)

    \(log(ODDS) =\beta_0 +\beta_A x_A\)

The difference in effect between B yes and B no is \(\beta_B + \beta_{AB}\)

\((\beta_0 +\beta_A x_A + \beta_B x_B + \beta_{AB} x_A x_B) - (\beta_0 +\beta_A x_A ) = \beta_B + \beta_{AB}\)

  • Not in the presence of A: \(x_A = 0\)

    • In the presence of B: \(x_B = 1\)

    \(log(ODDS) =\beta_0 + \beta_B x_B\)

    • Not in the presence of B: \(x_B = 0\)

    \(log(ODDS) =\beta_0\)

The difference in effect between B yes and B no is \(\beta_B\)

\((\beta_0 + \beta_B x_B) - (\beta_0) = \beta_B\)

There is effect modification if \(\beta_B \ne \beta_B+ \beta_{AB}\), that is, if the presence of B has a different effect on the different levels of A.

methods for identifying interactions

  1. automatic variable selection procedures: i.e stepwise regression. It’s based on including variables with “significant” p-values. An interaction exists if an interaction coefficient has a “significant p-value”.

  2. change in effect estimate: comparison of the effect estimates between adjusted and unadjusted effect estimates.

We evaluate the crude effect measure and the effect measure stratified by the possible confounder or effect modifier. If the stratum-specific effect measures are different from each other and the relative change greater than 10%, the variable is selected as a interaction.

If \(\beta_B\) in the presence of B but not A \(\ne\) \(\beta_B+ \beta_{AB}\) in the presence of B and A, that is, if the presence of B has a different effect on the different levels of A.

Gordis

interaction example 1

Age adjusted rate ratios for lung cancer due to arsenic exposure.

Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3 8.4
Smokers- 8.3 17.5 26.2
  1. Relative risk : multiplicative

Does smoking interact multiplicatively with arsenic?

Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3 * 8.3 = 19 8.4 * 8.3 = 69
Smokers- 8.3 17.5 26.2

There is no multiplicative interaction between smoking and residential arsenic exposure on lung cancer risk: \(2.3 * 8.3 = 19 \approx 17.5\)

There is an antagonistic multiplicative interaction between smoking and smelter worker arsenic exposure on lung cancer risk: \(8.4 * 8.3 = 69 \ne 26.2\)

Is smoking an effect modifier of the arsenic relative risk?

Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3/1 8.4/1
Smokers- 8.3/8.3 17.5/8.3 26.2/8.3
Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3 8.4
Smokers- 1 2.1 3.2

Smoking does not modify the effect of residential arsenic exposure on lung cancer risk: \(2.3 \approx 2.1\)

Smoking does modify the effect of smelter workers’ arsenic exposure on lung cancer risk: this exposure has a much larger effect on non-smokers that smokers: \(8.4 > 3.2\)

  1. Excess risk : additive

If we were looking at excess risk instead of relative risk, we would look at the additive effect.

Is smoking an effect modifier of the arsenic excess risk?

Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3-1 8.4-1
Smokers- 8.3 17.5-8.3 26.2-8.3
Unexposed area Residentially exposed Smelter worker
Non smokers 1 1.3 7.4
Smokers- 8.3 9.2 17.9

Smoking does modify the effect of residential arsenic exposure on lung cancer excess risk synergistically: \(1.3 < 9.2\)

Smoking does modify the effect of smelter workers’ arsenic exposure on lung cancer excess risk synergistically: \(7.4 < 17.9\)

Does smoking interact additively with arsenic?

Unexposed area Residentially exposed Smelter worker
Non smokers 1 2.3-1 8.4-1
Smokers- 8.3-1 17.5-1 26.2-1
Unexposed area Residentially exposed Smelter worker
Non smokers 1 1.3 7.4
Smokers- 7.3 16.5 25.2

There is additive interaction between smoking and residential arsenic exposure on lung cancer risk: \(1.3 + 7.3 = 8.6 \ne 16.5\)

There is no additive interaction between smoking and smelter worker arsenic exposure on lung cancer risk: \(7.4 + 16.5 = 23.9 \approx 25.2\)

interaction example from @mcelreath2020 Chapter 8

Africa is geographically special, in a puzzling way: Bad geography tends to be related to bad economies outside of Africa, but African economies may actually benefit from bad geography. To appreciate the puzzle, look at regressions of terrain ruggedness—a particular kind of bad geography—against economic performance (log GDP136 per capita in the year 2000), both inside and outside of Africa. The variable rugged is a Terrain Ruggedness Index137 that quantifies the topographic heterogeneity of a landscape. The outcome variable here is the logarithm of real gross domestic product per capita, from the year 2000, rgdppc_2000. We use the logarithm of it, because the logarithm of GDP is the magnitude of GDP.

library(rethinking) 
data(rugged)
d <- rugged

# make the log version of criterion
d <- 
  d %>%
  mutate(log_gdp = log(rgdppc_2000))

# extract countries with GDP data
dd <-
  d %>%
  filter(complete.cases(rgdppc_2000)) %>% 
  # re-scale variables
  mutate(log_gdp_std = log_gdp / mean(log_gdp), 
         rugged_std  = rugged / max(rugged))

If this relationship is at all causal, it may be because rugged regions of Africa were pro- tected against the Atlantic and Indian Ocean slave trades. Slavers preferred to raid easily accessed settlements, with easy routes to the sea. Those regions that suffered under the slave trade understandably continue to suffer economically, long after the decline of slave-trading markets. However, an outcome like GDP has many influences, and is furthermore a strange measure of economic activity. And ruggedness is correlated with other geographic features, like coastlines, that also influence the economy. So it is hard to be sure what’s going on here.

The causal hypothesis, in DAG form, might be (where R is terrain ruggedness, G is GDP, C is continent): R and C both influence G. This could mean that they are independent influences or rather that they interact (one moderates the influence of the other). The DAG does not display an interaction. That’s because DAGs do not specify how variables combine to influence other variables. The DAG above implies only that there is some function that uses R and C to generate G. In typical notation, G = f(R, C).

So we need a statistical approach to judge different propositions for f(R, C).

So we need a statistical approach to judge different propositions for f(R, C). How do we make a model that produces the conditionality in Figure 8.2? We could cheat by splitting the data into two data frames, one for Africa and one for all the other continents. But it’s not a good idea to split the data in this way. Here are four reasons:

  1. First, there are usually some parameters, such as σ, that the model says do not depend in any way upon continent. By splitting the data table, you are hurting the accuracy of the es- timates for these parameters, because you are essentially making two less-accurate estimates instead of pooling all of the evidence into one estimate. In effect, you have accidentally as- sumed that variance differs between African and non-African nations. Now, there’s nothing wrong with that sort of assumption. But you want to avoid accidental assumptions.

  2. Second, in order to acquire probability statements about the variable you used to split the data, cont_africa in this case, you need to include it in the model. Otherwise, you have a weak statistical argument. Isn’t there uncertainty about the predictive value of distinguishing between African and non-African nations? Of course there is. Unless you analyze all of the data in a single model, you can’t easily quantify that uncertainty. If you just let the posterior distribution do the work for you, you’ll have a useful measure of that uncertainty.

  3. Third, we may want to use information criteria or another method to compare models. In order to compare a model that treats all continents the same way to a model that allows different slopes in different continents, we need models that use all of the same data (as explained in Chapter 7). This means we can’t split the data for two separate models. We have to let a single model internally split the data.

  4. Fourth, once you begin using multilevel models (Chapter 13), you’ll see that there are advantages to borrowing information across categories like “Africa” and “not Africa.” This is especially true when sample sizes vary across categories, such that overfitting risk is higher within some categories. In other words, what we learn about ruggedness outside of Africa should have some effect on our estimate within Africa, and visa versa. Multilevel models (Chapter 13) borrow information in this way, in order to improve estimates in all categories. When we split the data, this borrowing is impossible.

We look at the different possibilities to model the association between log(GDP) and ruggedness

  1. m8.1 ignoring continent.

Fit a single model to all the data, ignoring continent.

\(log(y_i) \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_0 + \beta (r_i - \bar{r})\)

m8.1 <- quap(
    alist(
        log_gdp_std ~ dnorm( mu , sigma ) ,
        mu <- a + b*( rugged_std - 0.215 ) ,
        a ~ dnorm( 1 , 0.1 ) ,
        b ~ dnorm( 0 , 0.3 ) ,
        sigma ~ dexp(1)
    ) , data=dd )

 precis( m8.1 )
##              mean          sd        5.5%      94.5%
## a     1.000000079 0.010412512  0.98335887 1.01664128
## b     0.002001904 0.054796238 -0.08557307 0.08957688
## sigma 0.136504552 0.007397121  0.12468252 0.14832658

Really no overall association between terrain ruggedness and log GDP.

Next we’ll see how to split apart the continents.

  1. m8.2 adding indicator variable for African nations

The first thing to realize is that just in- cluding an indicator variable for African nations, cont_africa here, won’t reveal the re- versed slope. It’s worth fitting this model to prove it to yourself, though.

\(log(y_i) \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_0 + \beta (r_i - \bar{r}) + \gamma A_i\)

where \(A_i\) is cont_africa, a 0/1 indicator variable.

The problem here, and in general, is that we need a prior for \(\gamma\). Okay, we can do priors. But what that prior will necessarily do is tell the model that \(\mu_i\) for a nation in Africa is more uncertain, before seeing the data, than \(\mu_i\) outside Africa. And that makes no sense.

There is a simple solution: Nations in Africa will get one intercept and those outside Africa another.

\(log(y_i) \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_{CID[i]} + \beta (r_i - \bar{r})\)

where cid is an index variable, continent ID. It takes the value 1 for African nations and 2 for all other nations. This means there are two parameters, \(\alpha_{1}\) and \(\alpha_{2}\) one for each unique index value. The notation cid[i] just means the value of cid on row i. Using this approach, instead of the conventional approach of adding another term with the 0/1 indicator variable, doesn’t force us to say that the mean for Africa is inherently less certain than the mean for all other continents.

#make variable to index Africa (1) or not (2)
dd$cid <- ifelse( dd$cont_africa==1 , 1 , 2 )

m8.2 <- quap( alist(
log_gdp_std ~ dnorm( mu , sigma ) ,
mu <- a[cid] + b*( rugged_std - 0.215 ) , a[cid] ~ dnorm( 1 , 0.1 ) ,
b ~ dnorm( 0 , 0.3 ) ,
sigma ~ dexp( 1 )
) , data=dd )

precis( m8.2 , depth=2 )
##              mean          sd       5.5%      94.5%
## a[1]   0.88041284 0.015937003  0.8549424 0.90588325
## a[2]   1.04916425 0.010185554  1.0328858 1.06544274
## b     -0.04651347 0.045686725 -0.1195297 0.02650274
## sigma  0.11238738 0.006091077  0.1026527 0.12212209

The parameter a[1] is the intercept for African nations. It seems reliably lower than a[2].

Now to compare these models, using WAIC:

##           WAIC       SE    dWAIC      dSE    pWAIC       weight
## m8.2 -252.2687 15.30518  0.00000       NA 4.258517 1.000000e+00
## m8.1 -188.7544 13.29153 63.51424 15.14616 2.690177 1.614571e-14

m8.2 gets all the model weight. And while the standard error of the difference in WAIC is 15, the difference itself is 64. So the continent variable seems to be picking up some important association in the sample.

Let’s plot the posterior predictions for m8.2, so you can see how, despite it’s predictive superiority to m8.1, it still doesn’t manage different slopes inside and outside of Africa. African nations are shown in blue, while nations outside Africa are shown in gray. What you’ve ended up with here is a rather weak negative relationship between economic development and ruggedness. The African nations do have lower overall economic development, and so the blue regression line is below, but parallel to, the black line. All including a dummy variable for African nations has done is allow the model to predict a lower mean for African nations. It can’t do anything to the slope of the line. The fact that WAIC tells you that the model with the dummy variable is hugely better only indicates that African nations on average do have lower GDP.

  1. m8.3 adding interaction variable for African nations

How can you recover the change in slope you saw at the start of this section? You need a proper interaction effect. This just means we also make the slope conditional on continent.

And again, there is a conventional approach to specifying an interaction that uses an indica- tor variable and a new interaction parameter. It would look like this:

\(log(y_i) \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_{CID[i]} + (\beta + \gamma A_i) (r_i - \bar{r})= \alpha_{CID[i]} +\beta(r_i - \bar{r})+ \gamma A_i(r_i - \bar{r})\)

where Ai is a 0/1 indicator for African nations. This is equivalent to our index approach, but it is much harder to state sensible priors. Any prior we put on γ makes the slope inside Africa more uncertain than the slope outside Africa. And again that makes no sense. But in the indexing approach, we can easily assign the same prior to the slope, no matter which continent.

\(log(y_i) \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_{CID[i]} + \beta_{CID[i]}(r_i - \bar{r})\)

m8.3 <- quap(
    alist(
        log_gdp_std ~ dnorm( mu , sigma ) ,
        mu <- a[cid] + b[cid]*( rugged_std - 0.215 ) ,
        a[cid] ~ dnorm( 1 , 0.1 ) ,
        b[cid] ~ dnorm( 0 , 0.3 ) ,
        sigma ~ dexp( 1 )
) , data=dd )

precis( m8.3 , depth=2 )
##             mean          sd       5.5%       94.5%
## a[1]   0.8865639 0.015675695  0.8615111  0.91161667
## a[2]   1.0505698 0.009936606  1.0346892  1.06645039
## b[1]   0.1325054 0.074204443  0.0139124  0.25109846
## b[2]  -0.1425767 0.054749403 -0.2300768 -0.05507653
## sigma  0.1094941 0.005935299  0.1000084  0.11897987

The slope is essentially reversed inside Africa, 0.13 instead of −0.14.

How much does allowing the slope to vary improve expected prediction? Let’s use PSIS to compare this new model to the previous two. You could use WAIC here as well. It’ll give almost identical results.

##           PSIS       SE    dPSIS       dSE    pPSIS       weight
## m8.3 -258.9122 15.26994  0.00000        NA 5.248904 9.731544e-01
## m8.2 -251.7313 15.27774  7.18088  6.563466 4.462810 2.684562e-02
## m8.1 -188.7363 13.28687 70.17592 15.393216 2.681052 5.619209e-16

Model family m8.3 has more than 95% of the weight. That’s very strong support for including the interaction effect, if prediction is our goal. But the modicum of weight given to m8.2 suggests that the posterior means for the slopes in m8.3 are a little overfit. And the standard error of the difference in PSIS between the top two models is almost the same as the difference itself.

# plot Africa - cid=1
d.A1 <- dd[ dd$cid==1 , ]
plot( d.A1$rugged_std , d.A1$log_gdp_std , pch=16 , col=rangi2 ,
    xlab="ruggedness (standardized)" , ylab="log GDP (as proportion of mean)" ,
    xlim=c(0,1) )
mu <- link( m8.3 , data=data.frame( cid=1 , rugged_std=rugged_seq ) )
mu_mean <- apply( mu , 2 , mean )
mu_ci <- apply( mu , 2 , PI , prob=0.97 )
lines( rugged_seq , mu_mean , lwd=2 )
shade( mu_ci , rugged_seq , col=col.alpha(rangi2,0.3) )


mtext("African nations")

# plot non-Africa - cid=2
d.A0 <- dd[ dd$cid==2 , ]
plot( d.A0$rugged_std , d.A0$log_gdp_std , pch=1 , col="black" ,
    xlab="ruggedness (standardized)" , ylab="log GDP (as proportion of mean)" ,
    xlim=c(0,1) )
mu <- link( m8.3 , data=data.frame( cid=2 , rugged_std=rugged_seq ) )
mu_mean <- apply( mu , 2 , mean )
mu_ci <- apply( mu , 2 , PI , prob=0.97 )
lines( rugged_seq , mu_mean , lwd=2 )
shade( mu_ci , rugged_seq )
mtext("Non-African nations")

COLLIDER

The core concept is easy to understand: When you condition on a collider, it creates statistical—but not necessarily causal— associations among its causes.

Collider bias arises from conditioning on a common consequence. If we can just get our graph sorted, we can avoid it. But it isn’t always so easy to see a potential collider, because there may be unmeasured causes. Unmeasured causes can still induce collider bias. So I’m sorry to say that we also have to consider the possibility that our DAG may be haunted.

children and education example from @mcelreath2020

We want to infer the direct influence of both parents (P) and grandparents (G) on the educational achievement of children (C). Since grandparents also presumably influence their own children’s education, there is an arrow G → P. This sounds pretty easy, so far. It’s similar in structure to our divorce rate example from last chapter:

But suppose there are unmeasured, common influences on parents and their children, such as neighborhoods, that are not shared by grandparents (who live on the south coast of Spain now). Then our DAG becomes haunted by the unobserved U:

Now P is a common consequence of G and U, so if we condition on P, it will bias inference about G → C, even if we never get to measure U. I don’t expect that fact to be immediately obvious. So let’s crawl through a quantitative example.

First, let’s simulate 200 triads of grandparents, parents, and children. This simulation will be simple. We’ll just project our DAG as a series of implied functional relationships. The DAG above implies that:

  1. P is some function of G and U

  2. C is some function of G, P, and U

  3. G and U are not functions of any other known variables

We can make these implications into a simple simulation, using rnorm to generate simulated observations. But to do this, we need to be a bit more precise than “some function of.” So I’ll invent some strength of association:

N <- 200 # number of grandparent-parent-child triads 
b_GP <- 1 # direct effect of G on P
b_GC <- 0 # direct effect of G on C
b_PC <- 1 # direct effect of P on C
b_U<-2 #direct effect of U on P and C

These parameters are like slopes in a regression model. Notice that I’ve assumed that grand- parents G have zero effect on their grandkids C. The example doesn’t depend upon that effect being exactly zero, but it will make the lesson clearer. Now we use these slopes to draw random observations:

set.seed(1)
U <- 2*rbern( N , 0.5 ) - 1
G <- rnorm( N )
P <- rnorm( N , b_GP*G + b_U*U )
C <- rnorm( N , b_PC*P + b_GC*G + b_U*U ) 
d <- data.frame( C=C , P=P , G=G , U=U )

I’ve made the neighborhood effect, U, binary. This will make the example easier to under- stand. But the example doesn’t depend upon that assumption. The other lines are just linear models embedded in rnorm.

Now what happens when we try to infer the influence of grandparents? Since some of the total effect of grandparents passes through parents, we realize we need to control for parents.

Here is a simple regression of C on P and G. Normally I would advise standardizing the variables, because it makes establishing sensible priors a lot easier. But I’m going to keep the simulated data on its original scale, so you can see what happens to inference about the slopes above. If we changed the scale, we shouldn’t expect to get those values back. But if we leave the scale alone, we should be able to recover something close to those values. So I apologize for using vague priors here, just to push forward in the example.

m6.11 <- quap( alist(
C ~ dnorm( mu , sigma ),
mu <- a + b_PC*P + b_GC*G,
a ~ dnorm( 0 , 1 ), 
c(b_PC,b_GC) ~ dnorm( 0 , 1 ), 
sigma ~ dexp( 1 )
), data=d ) 
precis(m6.11)
##             mean         sd       5.5%       94.5%
## a     -0.1174752 0.09919574 -0.2760091  0.04105877
## b_PC   1.7868915 0.04455355  1.7156863  1.85809664
## b_GC  -0.8389537 0.10614045 -1.0085867 -0.66932077
## sigma  1.4094891 0.07011139  1.2974375  1.52154063

The inferred effect of parents looks too big, almost twice as large as it should be. That isn’t surprising. Some of the correlation between P and C is due to U, and the model doesn’t know about U. That’s a simple confound. More surprising is that the model is confident that the direct effect of grandparents is to hurt their grandkids. The regression is not wrong. But a causal interpretation of that association would be.

Note that I did standardize the variables to make this plot. So the units on the axes are standard deviations. The horizontal axis is grandparent education. The vertical is grandchild education. There are two clouds of points. The blue cloud comprises children who live in good neighborhoods (U = 1). The black cloud comprises children who live in bad neighborhoods (U = −1). No- tice that both clouds of points show positive associations between G and C. More educated grandparents have more educated grandkids, but this effect arises entirely through parents. Why? Because we assumed it is so. The direct effect of G in the simulation is zero.

So how does the negative association arise, when we condition on parents? Conditioning on parents is like looking within sub-populations of parents with similar education. So let’s try that. In the Figure, I’ve highlighted in filled points those parents between the 45th and 60th centiles of education. There is nothing special of this range. It just makes the phenomenon easier to see. Now if we draw a regression line through only these points, regressing C on G, the slope is negative. There is the negative association that our multiple regression finds. But why does it exist?

It exists because, once we know P, learning G invisibly tells us about the neighborhood U, and U is associated with the outcome C. I know this is confusing. As I keep saying, if you are confused, it is only because you are paying attention.

So consider two different parents with the same education level, say for example at the median 50th centile. One of these parents has a highly educated grandparent. The other has a poorly educated grandparent. The only probable way, in this example, for these parents to have the same education is if they live in different types of neighborhoods. We can’t see these neighborhood effects—we haven’t measured them, recall—but the influence of neighborhood is still transmitted to the children C. So for our mythical two parents with the same education, the one with the highly educated grandparent ends up with a less well educated child. The one with the less educated grandparent ends up with the better educated child. G predicts lower C.

The unmeasured U makes P a collider, and conditioning on P produces collider bias. So what can we do about this? You have to measure U. Here’s the regression that conditions also on U:

m6.12 <- quap( alist(
C ~ dnorm( mu , sigma ),
mu <- a + b_PC*P + b_GC*G + b_U*U,
a ~ dnorm( 0 , 1 ),
c(b_PC,b_GC,b_U) ~ dnorm( 0 , 1 ),
sigma ~ dexp( 1 ) ), data=d )
precis(m6.12)
##              mean         sd       5.5%        94.5%
## a     -0.12197510 0.07192588 -0.2369265 -0.007023655
## b_PC   1.01161103 0.06597258  0.9061741  1.117047948
## b_GC  -0.04081373 0.09728716 -0.1962974  0.114669941
## b_U    1.99648992 0.14770462  1.7604294  2.232550439
## sigma  1.01959911 0.05080176  0.9384081  1.100790130

And those are the slopes we simulated with.

Rethinking: Statistical paradoxes and causal explanations. The grandparents example serves as an example of Simpson’s paradox: Including another predictor (P in this case) can reverse the direction of association between some other predictor (G) and the outcome (C). Usually, Simpson’s paradox is presented in cases where adding the new predictor helps us. But in this case, it misleads us. Simpson’s paradox is a statistical phenomenon. To know whether the reversal of the association correctly reflects causation, we need something more than just a statistical model.

MULTICOLLINEARITY

From @mcelreath2020:

Multicollinearity means a very strong association between two or more predictor variables. The raw correlation isn’t what matters. Rather what matters is the association, conditional on the other variables in the model. The consequence of multicollinearity is that the posterior distribution will seem to suggest that none of the variables is reliably associated with the outcome, even if all of the variables are in reality strongly associated with the outcome.

The problem of multicollinearity is a member of a family of problems with fitting models, a family sometimes known as non-identifiability.

non-identifiability

When a parameter is non-identifiable, it means that the structure of the data and model do not make it possible to estimate the parameter’s value. Sometimes this problem arises from mistakes in coding a model, but many important types of models present non-identifiable or weakly identifiable parameters, even when coded completely correctly. Nature does not owe us easy inference, even when the model is correct.

leg example

\(height \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_{0} + \beta_{l} x_{leg\:left}+ \beta_{r} x_{leg\:right}\)

Imagine trying to predict an individual’s height using the length of his or her legs as predictor variables. Surely height is positively associated with leg length, or at least our simulation will assume it is. Nevertheless, once you put both legs (right and left) into the model, something vexing will happen.

The code below will simulate the heights and leg lengths of 100 individuals. For each, first a height is simulated from a Gaussian distribution. Then each individual gets a simulated proportion of height for their legs, ranging from 0.4 to 0.5. Finally, each leg is salted with a little measurement or developmental error, so the left and right legs are not exactly the same length, as is typical in real populations. At the end, the code puts height and the two leg lengths into a common data frame.

Now let’s analyze these data, predicting the outcome height with both predictors, leg_left and leg_right. Before approximating the posterior, however, consider what we expect. On average, an individual’s legs are 45% of their height (in these simulated data). So we should expect the beta coefficient that measures the association of a leg with height to end up around the average height (10) divided by 45% of the average height (4.5). This is 10/4.5 ≈ 2.2. Now let’s see what happens instead. I’ll use very vague, bad priors here, just so we can be sure that the priors aren’t responsible for what is about to happen.

N <- 100
set.seed(909)
height <- rnorm(N,10,2)
leg_prop <- runif(N,0.4,0.5)
leg_left <- leg_prop*height +
    rnorm( N , 0 , 0.02 )
leg_right <- leg_prop*height +
    rnorm( N , 0 , 0.02 )
d <- data.frame(height,leg_left,leg_right)


m6.1 <- quap(
    alist(
        height ~ dnorm( mu , sigma ) ,
        mu <- a + bl*leg_left + br*leg_right ,
        a ~ dnorm( 10 , 100 ) ,
        bl ~ dnorm( 2 , 10 ) ,
        br ~ dnorm( 2 , 10 ) ,
        sigma ~ dexp( 1 )
),
    data=d )
precis(m6.1)
##            mean         sd       5.5%     94.5%
## a     0.9812791 0.28395540  0.5274635 1.4350947
## bl    0.2118585 2.52703706 -3.8268348 4.2505518
## br    1.7836774 2.53125061 -2.2617500 5.8291047
## sigma 0.6171026 0.04343427  0.5476862 0.6865189
plot(precis(m6.1))

Those posterior means and standard deviations look crazy. Both legs have almost identical lengths, and height is so strongly associated with leg length, then why is this posterior distribution so weird? Did the posterior approximation work correctly?

The posterior distribution here is the right answer to the question we asked. The problem is the question. Recall that a multiple linear regression answers the question: What is the value of knowing each predictor, after already knowing all of the other predictors? So in this case, the question becomes: What is the value of knowing each leg’s length, after already knowing the other leg’s length?

The answer to this weird question is equally weird, but perfectly logical. The posterior distribution is the answer to this question, considering every possible combination of the parameters and assigning relative plausibilities to every combination, conditional on this model and these data. It might help to look at the joint posterior distribution for bl and br. The posterior distribution for these two parameters is very highly correlated, with all of the plausible values of bl and br lying along a narrow ridge. When bl is large, then br must be small. What has happened here is that since both leg variables contain almost exactly the same information, if you insist on including both in a model, then there will be a practically infinite number of combinations of bl and br that produce the same predictions.

post <- extract.samples(m6.1)
plot( bl ~ br , post , col=col.alpha(rangi2,0.1) , pch=16 )

One way to think of this phenomenon is that you have approximated this model:

\(height \sim N(\mu_i, \sigma)\)

\(\mu_i = \alpha_{0} + \beta_{1} x_{i}+ \beta_{2} x_{i}\)

The variable y is the outcome, like height in the example, and x is a single predictor, like the leg lengths in the example. Because the left and right legs are so correlated, it’s like using x twice. From the golem’s perspective, the model for μi is:

\(\mu_i = \alpha_{0} + (\beta_{l} + \beta_{r}) x\)

The parameters β1 and β2 cannot be pulled apart, because they never separately influence the mean μ. Only their sum, β1+β2, influences μ. So this means the posterior distribution ends up reporting the very large range of combinations of β1 and β2 that make their sum close to the actual association of x with y.

And the posterior distribution in this simulated example has done exactly that: It has produced a good estimate of the sum of bl and br. Here’s how you can compute the posterior distribution of their sum, and then plot it:

sum_blbr <- post$bl + post$br
dens( sum_blbr , col=rangi2 , lwd=2 , xlab="sum of bl and br" )

The posterior mean is in the right neighborhood, a little over 2, and the standard deviation is much smaller than it is for either component of the sum, bl or br. If you fit a regression with only one of the leg length variables, you’ll get approximately the same posterior mean:

m6.2 <- quap( alist(
height ~ dnorm( mu , sigma ) , mu <- a + bl*leg_left,
a ~ dnorm( 10 , 100 ) ,
bl ~ dnorm( 2 , 10 ) ,
sigma ~ dexp( 1 ) ) , data=d )
precis(m6.2)
##            mean         sd      5.5%    94.5%
## a     0.9979326 0.28364620 0.5446112 1.451254
## bl    1.9920676 0.06115704 1.8943269 2.089808
## sigma 0.6186038 0.04353998 0.5490185 0.688189

That 1.99 is almost identical to the mean value of sum_blbr.

The basic lesson is only this: When two predictor variables are very strongly correlated (conditional on other variables in the model), including both in a model may lead to confu- sion. The posterior distribution isn’t wrong, in such cases. It’s telling you that the question you asked cannot be answered with these data. And that’s a great thing for a model to say, that it cannot answer your question. And if you are just interested in prediction, you’ll find that this leg model makes fine predictions. It just doesn’t make any claims about which leg is more important.

milk example

In this example, we are concerned with the perc.fat (percent fat) and perc.lactose (per- cent lactose) variables. We’ll use these to model the total energy content, kcal.per.g. The code above has already standardized these three variables. You’re going to use these three variables to explore a natural case of multicollinearity.

library(rethinking)
data(milk)
d <- milk
d$K <- scale( d$kcal.per.g )
d$F <- scale( d$perc.fat )
d$L <- scale( d$perc.lactose )
    1. kcal.per.g regressed on perc.fat

Start by modeling kcal.per.g as a function of perc.fat and perc.lactose, but in two bivariate regressions.

# kcal.per.g regressed on perc.fat
m6.3 <- quap(
    alist(
        K ~ dnorm( mu , sigma ) ,
        mu <- a + bF*F ,
        a ~ dnorm( 0 , 0.2 ) ,
        bF ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
) , data=d )
# kcal.per.g regressed on perc.lactose
m6.4 <- quap(
    alist(
        K ~ dnorm( mu , sigma ) ,
        mu <- a + bL*L ,
        a ~ dnorm( 0 , 0.2 ) ,
        bL ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
) , data=d )
precis( m6.3 )
##               mean         sd       5.5%     94.5%
## a     1.535526e-07 0.07725195 -0.1234634 0.1234637
## bF    8.618970e-01 0.08426088  0.7272318 0.9965621
## sigma 4.510179e-01 0.05870756  0.3571919 0.5448440
precis( m6.4 )
##                mean         sd       5.5%      94.5%
## a      7.438895e-07 0.06661633 -0.1064650  0.1064665
## bL    -9.024550e-01 0.07132848 -1.0164517 -0.7884583
## sigma  3.804653e-01 0.04958259  0.3012227  0.4597078

The posterior distributions for bF and bL are essentially mirror images of one another. The posterior mean of bF is as positive as the mean of bL is negative. Both are narrow posterior distributions that lie almost entirely on one side or the other of zero. Given the strong association of each predictor with the outcome, we might conclude that both variables are reliable predictors of total energy in milk, across species. The more fat, the more kilocalories in the milk. The more lactose, the fewer kilocalories in milk. But watch what happens when we place both predictor variables in the same regression model:

m6.5 <- quap(
    alist(
        K ~ dnorm( mu , sigma ) ,
        mu <- a + bF*F + bL*L ,
        a ~ dnorm( 0 , 0.2 ) ,
        bF ~ dnorm( 0 , 0.5 ) ,
        bL ~ dnorm( 0 , 0.5 ) ,
        sigma ~ dexp( 1 )
),
    data=d )
precis( m6.5 )
##                mean         sd        5.5%      94.5%
## a     -3.172136e-07 0.06603577 -0.10553823  0.1055376
## bF     2.434983e-01 0.18357865 -0.04989579  0.5368925
## bL    -6.780825e-01 0.18377670 -0.97179320 -0.3843719
## sigma  3.767418e-01 0.04918394  0.29813637  0.4553472

Now the posterior means of both bF and bL are closer to zero. And the standard deviations for both parameters are twice as large as in the bivariate models (m6.3 and m6.4).

This is the same statistical phenomenon as in the leg length example. What has happened is that the variables perc.fat and perc.lactose contain much of the same information. They are almost substitutes for one another. As a result, when you include both in a regression, the posterior distribution ends up describing a long ridge of combinations of bF and bL that are equally plausible. In the case of the fat and lactose, these two variables form essentially a single axis of variation. The easiest way to see this is to use a pairs plot:

 pairs( ~ kcal.per.g + perc.fat + perc.lactose , data=d , col=rangi2 )

Percent fat is positively correlated with the outcome, while percent lactose is negatively correlated with it.

Now look at the right-most scatterplot in the middle row. This plot is the scatter of percent fat (vertical) against percent lactose (horizontal). Notice that the points line up almost entirely along a straight line. These two variables are negatively correlated, and so strongly so that they are nearly redundant. Either helps in predicting kcal.per.g, but neither helps as much once you already know the other.

how to detect multicollinearity

In the scientific literature, you might encounter a variety of dodgy ways of coping with multicollinearity. Few of them take a causal perspective. Some fields actually teach students to inspect pairwise correlations before fitting a model, to identify and drop highly correlated predictors. This is a mistake. Pairwise correlations are not the problem. It is the conditional associations—not correlations—that matter. And even then, the right thing to do will depend upon what is causing the collinearity. The associations within the data alone are not enough to decide what to do.

  • look at bivariate associations:

    • quantitative variables:

      • if the variable is normally distributed: pearson correlation coefficient
      • correlation matrix

    • ordinal variables: spearman rank correlation coefficient.

    • between nominal (binomial or multinomial) variables: chi-square test

    • between categorical and continuous variables:

      • 2 categories: t-test
      • \(>\) 2 categories: ANOVA

  • use VIF = variance inflation. If it’s >10 it’s a sign of collinearity.

What is likely going on in the milk example is that there is a core tradeoff in milk composition that mammal mothers must obey. If a species nurses often, then the milk tends to be watery and low in energy. Such milk is high in sugar (lactose). If instead a species nurses rarely, in short bouts, then the milk needs to be higher in energy. Such milk is very high in fat. This implies a causal model something like this:

The central tradeoff decides how dense, D, the milk needs to be. We haven’t observed this variable, so it’s shown circled. Then fat, F, and lactose, L, are determined. Finally, the com- position of F and L determines the kilocalories, K. If we could measure D, or had an evolutionary and economic model to predict it based upon other aspects of a species, that would be better than stumbling through regressions.

In general, there’s no guarantee that the available data contain much information about a parameter of interest. When that’s true, your Bayesian machine will return a posterior distribution very similar to the prior. Comparing the posterior to the prior can therefore be a good idea, a way of seeing how much information the model extracted from the data. When the posterior and prior are similar, it doesn’t mean the calculations are wrong—you got the right answer to the question you asked. But it might lead you to ask a better question.

STUDY DESIGN

OBSERVATIONAL STUDIES

ecological

  • unit of study: group

  • measure: rate of disease, rate of exposure.

cross -sectional

SImultaneously collect data on disease and exposure status = snapshot of the population

  • unit of study: individual

  • measure:

    • prevalence ratio of disease: in exposed vs non-exposed

    \[\frac{P(D^+|E^+)}{P(D^+|E^-)}\]

    • prevalence ratio of exposure: in diseased vs not diseased

      \[\frac{P(E^+|D^+)}{P(E^+|D^-)}\]

    • OR of disease in exposed vs non-exposed: odds D+ in E+ group/ odds D+ in E- group

\[\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}=\frac{\frac{a}{b}}{\frac{c}{d}}=\frac{ad}{bc}=\frac{odds\:D^+\:in\:exposed\:population}{odds\:D^+\:in\:unexposed\:population}\] + OR of exposure in diseased vs not diseased= odds E+ in D+ group/ odds E+ in D- group

\[\frac{\frac{P(E^+|D^+)}{P(E^-|D^+)}}{\frac{P(E^+|D^-)}{P(E^-|D^-)}}=\frac{\frac{a}{c}}{\frac{b}{d}}=\frac{ad}{bc}=\frac{odds\:E^+\:in\:diseased\:population}{odds\:E^+\:in\:not\:diseased\:population}\]

Grodis

Grodis

cons: not good for diseases or exposures that are rare, or diseases with long incubation periods (the duration of disease alters the perception of prevalence).

The validity of these studies are greatly affected by the sensitivity and specificity of the tests used to determine the disease and exposure status.

case-control

define population by disease status and determine past exposure

the compared populations must be defined with care to make sure they are comparable so the results are not confounded

  • unit of study: individual

  • measure:

    • Odds ratio (OR) of disease: in exposed vs non-exposed

    \[\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}=\frac{\frac{a}{b}}{\frac{c}{d}}=\frac{ad}{bc}=\frac{odds\:D^+\:in\:exposed\:population}{odds\:D^+\:in\:unexposed\:population}\]

    • Odds ratio (OR) of exposure: in diseased vs not diseased

    \[\frac{\frac{P(E^+|D^+)}{P(E^-|D^+)}}{\frac{P(E^+|D^-)}{P(E^-|D^-)}}=\frac{\frac{a}{c}}{\frac{b}{d}}=\frac{ad}{bc}=\frac{odds\:E^+\:in\:diseased\:population}{odds\:E^+\:in\:not\:diseased\:population}\]

Grodis SELECTION OF CONTROLS

Minimize bias by selecting using the study base principle: the distribution of the exposure in the control group should be representative of the exposure in the study base, that is the population that produced the cases.

Matching: selecting cases that are matched to controls by levels of a certain factor can improve efficiency of the analysis and reduce confounding.

Overmatching: matching that harms 1. statistical efficiency 2. cost efficiency 3. validity

  • matching on non-confounder associated with exposure but not with the outcome: This causes selection bias. The factor must be included in the analysis. This is the worst candidate for matching.

  • matching on a factor on the causal pathway between exposure and outcome:

    • the factor is not associated with the outcome: This causes bias, and the factor must be included in the analysis (in the stratification, regression, etc…)
    • the factor is associated with the outcome: This causes selection bias and cannot be fixed by including the factor in the analysis.

  • matching on a factor with some association to exposure: example: neighborhood, friends, family….

cohort = longitudinal

the compared populations must be defined with care to make sure they are comparable so the results are not confounded

  • unit of study: individual

  • measure:

    • relative risk (RR) of disease: in exposed vs non-exposed

      • cumulative incidence ratio: if the population is static

      • incidence density ratio: if the population is dynamic

    \[\frac{P(D^+|E^+)}{P(D^+|E^-)}\]

    • time to event: survival analysis.

Gordis

define population:

  • by not randomly assigned exposure status \(\to\) determine the development of disease: allows the study of 1 exposure and multiple outcomes

  • randomly assigned individuals in the defined population \(\to\) determine the development of disease and exposure status: : allows the study ofmultiple exposures and outcomes

Gordis

  • prospective: enroll participants based on exposure status and follow up over time

  • retrospective: enroll participants based on disease status and look at historic records to obtain exposure status.

    • cons: recall bias.

Gordis

assumptions

  • Lost to follow up (LTF) are independent

cohort-based case-control studies

pros:

  • exposure are have a temporal sequence and therefore are likely to be risk factors

  • cheaper as there are fewer lab costs ( you only test those who develop disease for exposure)

  • cases and controls are from the same population and therefore comparable

cons:

nested case-control

Controls selected by time of case development, that is the controls are matched with the cases on calendar time and follow-up time (time is considered a confounder).

Disadvantage: the control could turn into a case.

  • measure:

    • Odds ratio (OR)

By selecting the controls matching on time, we can interpret the odds ratio as a rate or risk measure, without making the rare disease assumption, by assuming only that the incidence is constant over time (see odds ratio section).

Gordis

case-cohort

Controls selected by random allocation at the end of the study from non-cases in the defined cohort, that is the controls are NOT matched with the cases on calendar time and follow-up time.

  • measure:

    • Odds ratio (OR)

Gordis

comparison case-control and cohort

Gordis

Gordis: comparison case-control and cohort

relationship between study design and effect measure

You CAN compute P(random event|fixed event)= probability of a random event conditioned on a fixed event.

You CAN’T compute P(fixed event|random event)= probability of a fixed event conditioned on a random event.

  1. COHORT study: define participants by exposure status and follow up to observe occurrence of cases.

random event = disease

fixed event = exposure.

Risk Ratio = P(D+|E+) and P(D+|E-) \(\to\) CAN compute

\[RR= \frac{P(D^+|E^+)}{P(D^+|E^-)}=\frac{\frac{a}{a+b}}{\frac{c}{c+d}}=\frac{D^+\:in\:exposed\:population}{D^-\:in\:unexposed\:population}\]

  1. CASE-CONTROL study: define participants by disease status and investigate occurrence of past exposure.

random event = exposure

fixed event = disease

Risk Ratio = P(D+|E+) and P(D+|E-) \(\to\) can’t compute!!!

\[RR= \frac{P(D^+|E^+)}{P(D^+|E^-)}=\frac{\frac{a}{a+b}}{\frac{c}{c+d}}=\frac{D^+\:in\:exposed\:population}{D^-\:in\:unexposed\:population}\]

OR= odds D+ in E+ group/ odds D+ in E- group \(\to\) can’t compute

\[\frac{\frac{P(D^+|E^+)}{P(D^-|E^+)}}{\frac{P(D^+|E^-)}{P(D^-|E^-)}}=\frac{\frac{a}{b}}{\frac{c}{d}}=\frac{ad}{bc}=\frac{odds\:D^+\:in\:exposed\:population}{odds\:D^+\:in\:unexposed\:population}\]

OR= odds E+ in D+ group/ odds E+ in D- group \(\to\) CAN compute because exposure can be treated as a random event.

\[\frac{\frac{P(E^+|D^+)}{P(E^-|D^+)}}{\frac{P(E^+|D^-)}{P(E^-|D^-)}}=\frac{\frac{a}{c}}{\frac{b}{d}}=\frac{ad}{bc}=\frac{odds\:E^+\:in\:diseased\:population}{odds\:E^+\:in\:not\:diseased\:population}\]

OR are symmetric from the perspective of exposure and outcome, so it doesn’t matter! :)

  1. CROSS-SECTIONAL STUDY:

Risk Ratio: can be estimated only if the cross-sectional study is a probability sample (each person has the same probability of being included in the study)

OR: can always be estimated

Logistic regression validly estimates odds ratios but does not necessarily validly estimate risk ratios.

EXPERIMENTAL STUDIES

randomized clinical trial = RCT

Th goal is to test a hypothesis or answer a medical question

The population is defined and the exposure/treatment is randomly allocated in the defined population.

Gordis

random allocation

Why is random allocation important? Because it decreases bias, and therefore it is easier to obtain an unbiased effect and to extrapolate the results to the general population:

  • selection bias: participants are not included in either exposure group based on a given factor (investigator bias, etc)

  • confounding and internal validity: the 2 groups are more likely to be comparable to one another in terms of unmeasured factors that may influence the outcome (age, sex, etc)

  • stratified randomization

Using data collected prior to the randomization, the participants are:

  1. stratified into groups
  2. the exposure/treatment is randomly allocated in each group

Goal: decrease the variation in an outcome due to a given factor: members of each stratum will be ore comparable to each other.

Gordis Figure 7-4

limitations: there is a limit to the amount of variables you can stratify by, as you want at least 20 individuals in each group.

cons: it coplicates and delays randomization.

  • intent to treat analysis : even if the subject doesn’t comply with treatment, it is included in the orginial treatment group

  • early stop point : and interim analysis can be performed midway throught the trial if there is sufficient sample size, and can lead to the discontinuation of the trial if there is sufficient evidence that the treat treatment works well or not.

Experimental Clinical Trials Intervention Trials Prevention Trials Field Trials

MODELS

FREQUENTIST APPROACH

The frequentist approach requires that all probabilities be defined by connection to the frequencies of events in very large samples. Frequentist uncertainty is premised on the imaginary resampling of data—if we were to repeat the measurement many many times, we would end up collecting a list of values that will have some pattern to it. It means also that parameters and models cannot have probability distributions, only measurements can. This resampling is never done, and in general it doesn’t even make sense—it is absurd to consider repeat sampling of the diversification of song birds in the Andes.But in many contexts, like controlled greenhouse experiments, it’s a useful device for describing uncertainty. Whatever the context, it’s just part of the model, an assumption about what the data would look like under resampling.

Sampling distribution is the distribution of these measurements.

Example: Bayesian vs frequentist Galileo turned a primitive telescope to the night sky and became the first human to see Saturn’s rings. Well, he probably saw a blob, with some smaller blobs attached to it. Since the telescope was primitive, it couldn’t really focus the image very well. Saturn always appeared blurred. This is a statistical problem, of a sort. There’s uncertainty about the planet’s shape, but notice that none of the uncertainty is a result of variation in repeat measurements. We could look through the telescope a thousand times, and it will always give the same blurred image (for any given position of the Earth and Saturn). So the sampling distribution of any measurement is constant, because the measurement is deterministic—there’s nothing “random” about it. Frequentist statistical inference has a lot of trouble getting started here. In contrast, Bayesian inference proceeds as usual, because the deterministic “noise” can still be modeled using probability, as long as we don’t identify probability with frequency.

resampling of data—if we were to repeat the measurement many many times, we would end up collecting a list of values that will have some pattern to it. It means also that parameters and models cannot have probability distributions, only measurements can. The distribution of these measurements is called a sampling distribution. This resampling is never done, and in general it doesn’t even make sense—it is absurd to consider repeat sampling of the diversification of song birds in the Andes.

BAYESIAN APPROACH In modest terms, Bayesian data analysis is no more than counting the numbers of ways the data could happen, according to our assumptions. Things that can happen more ways are more plausible.

model selection

information: “The reduction in uncertainty when we learn an outcome.” @mcelreath2020

information entropy: If there are n different possible events and each event i has probability pi, and we call the list of probabilities p, then the unique measure of uncertainty we seek is: \(H(p) = -E log(p_i) = -\sum_{i=1}^n p_i log(p_i)\) The uncertainty contained in a probability distribution is the average log-probability of an event. The lower this measure the less uncertainty.

divergence: : The additional uncertainty induced by using probabilities from one distribution to describe another distribution: \(D_{KL} (p,q) = \sum_{i} p_i (log(p_i)-log(q_i)) = \sum_{i} p_i log(p_i/q_i)\) The divergence is the average difference in log probability between the target (p) and model (q). This divergence is just the difference between two entropies: The entropy of the target distribution p and the cross entropy arising from using q to predict p (see the Overthinking box on the next page for some more detail). When p = q, we know the actual probabilities of the events and \(D_{KL} = 0\). As q grows more different from p, the divergence also grows.

To use DKL to compare models, it seems like we would have to know p, the target proba- bility distribution. In all of the examples so far, I’ve just assumed that p is known. But when we want to find a model q that is the best approximation to p, the “truth,” there is usually no way to access p directly. We wouldn’t be doing statistical inference, if we already knew p. Good thing is, we are only interested in comparing the divergences of different candidates, say q and r. In that case, most of p just subtracts out, because there is a E log(pi) term in the divergence of both q and r. This term has no effect on the distance of q and r from one another. So while we don’t know where p is, we can estimate how far apart q and r are, and which is closer to the truth. It’s as if we can’t tell how far any particular archer is from hitting the target, but we can tell which archer gets closer and by how much. All of this also means that all we need to know is a model’s average log-probability: E log(qi) for q and E log(ri) for r.

deviance: -2 * the total log-probability score for the model and data.\(-2\sum_{i}log(q_i)\)

LINEAR REGRESSION

outcome

continuous

distribution

normal \(y_i \to Normal(\mu_i, \sigma)\)

model

\(\hat{y_i}=\beta_0 +\beta_1x_1...+\beta_n x_n\) or \(\hat{y_i}=\alpha +\beta(x_i-\bar{x}) + \epsilon_i\)

linear predictor: \(\mu_i\) = E(y)

dispersion parameter: \(\sigma^2\) = Variance ( \(y | \mu\) )

assumptions

Gelman and Hill 2005:

Decreasing importance

1.validity: the outcome measure should accurately reflect the phenomenon of interest, the model should include all relevant predictors, and the model should generalize to the cases to which it will be applied.

2.additivity and linearity: its deterministic component is a linear function of the separate predictors: \(\hat{y_i}=\beta_0 +\beta_1x_1...+\beta_n x_n\)

In other words, for every given value of x, the spread of positive residuals is the same as of negative residuals.

  • If additivity is violated, it might make sense to transform the data (for example, if y = abc,then logy = loga + logb + logc )or to add interactions

  • If linearity is violated:

    • the dependent variable (y) can be transformed: usually to log
    • a predictor (x) can be transformed:
      • 1/x or log(x) instead of simply linearly
      • as a categorical variable
    • a more complicated relationship could be expressed:
      • by polynomials: including both x and x2 and/or x3 as predictors.
      • by using a nonlinear function such as a spline or other generalized additive model.

3.independence of errors: the errors from the prediction line are independent. In other words, for every given value of x, the values of y are statistically independent from each other.

This is violated when observations are correlated, such as vision from each eye in one person, or height measured in the same person over time.

4.equal variance of errors: If the variance of the regression errors are unequal, estimation is more efficiently performed using weighted least squares. In other words, for every given value of x, the values of y are have the same variance.

5.normality of errors: the regression assumption that is generally least important is that the errors are normally distributed. In fact, for the purpose of estimating the regression line (as compared to predicting individual data points), the assumption of normality is barely important at all. Thus, in contrast to many regression textbooks, we do not recommend diagnostics of the normality of regression residuals. In other words, for every given value of x, the values of y have a normal distribution.

Example: height ~ age. For any given age, for example 25, the values of height will follow a normal distribution. This will usually happen as long as the sample size is large enough thanks to the Central Limit Theorem.

Example of residuals with equal variance and linearity assumptions met:

parameter estimation

estimate the parameters by minimizing the sum of the prediction errors = deviance = least square estimates \((\hat{y_i}- \hat{y_i})^{2}\)

Stats book Satats book

interpretation of coefficients

EXAMPLE child test score from maternal education and maternal IQ. The fitted model is: kid.score = 26 + 6 · mom.hs + 0.6 · mom.iq + error

In this model the slope of the regression of child’s test score on mother’s IQ is forced to be equal across subgroups defined by mother’s high school completion,

\(\beta_0\) The intercept. If a child had a mother with an IQ of 0 and who did not complete high school (thus, mom.hs = 0), then we would predict this child’s test score to be 26. This is not a useful prediction, since no mothers have IQs of 0.

\(\beta_{momhs}\) The coefficient of maternal high school completion. Comparing children whose mothers have the same IQ, but who differed in whether they completed high school, the model predicts an expected difference of 6 in their test scores.

\(\beta_{momiq}\) The coeðcient of maternal IQ. Comparing children with the same value of mom.hs, but whose mothers differ by 1 point in IQ, we would expect to see a difference of 0.6 points in the child’s test score (equivalently, a difference of 10 in mothers’ IQs corresponds to a difference of 6 points for their children).

\(\beta_{momiq:momhs}\) interaction allows the slope to vary across subgroups.

EXAMPLE kid.score = -11 + 51 · mom.hs + 1.1 · mom.iq - 0.5 · mom.hs · mom.iq + error

  1. The intercept represents the predicted test scores for children whose mothers did not complete high school and had IQs of 0—not a meaningful scenario.

  2. The coefficient of mom.hs can be conceived as the difference between the predicted test scores for children whose mothers did not complete high school and had IQs of 0, and children whose mothers did complete high school and had IQs of 0. You can see this by just plugging in the appropriate numbers and comparing the equations. Since it is implausible to imagine mothers with IQs of zero, this coefficient is not easily interpretable.

  3. The coefficient of mom.iq can be thought of as the comparison of mean test scores across children whose mothers did not complete high school, but whose mothers differ by 1 point in IQ.

  4. The coefficient on the interaction term represents the difference in the slope for mom.iq, comparing children with mothers who did and did not complete high school.

Another way of looking at this is modeling different slopes for moms that did complete high school and moms that didn’t

no hs: kid.score = -11+51·0+1.1·mom.iq-0.5·0·mom.iq = -11 + 1.1 · mom.iq

hs: kid.score = -11+51·1+1.1·mom.iq-0.5·1·mom.iq = 40 + 0.6 · mom.iq.

The estimated slopes of 1.1 for children whose mothers did not complete high school and 0.6 for children of mothers who did are directly interpretable. The intercepts still suffer from the problem of only being interpretable at mothers’ IQs of 0.

CENTERING VARIABLES

Models with interactions can often be more easily interpreted if we first pre-process the data by centering each input variable about its mean or some other convenient reference point.

examples: kid.score = 26 + 6 · mom.hs + 0.6 · (mom.iq- avg.mom.iq) + error

\(\beta_0\) The intercept. If a child had a mother with an IQ at the average IQ ( thus mom.iq= avg.mom.iq) and who did not complete high school (thus, mom.hs = 0), then we would predict this child’s test score to be 26. This is an interpretable prediction.

inference

The least squares estimate is the maximum likelihood estimate if the errors \(\epsilon_i\) are independent with equal variance and normally distributed, and for the model \(y=X\beta+\epsilon\) it is the \(\hat{\beta}\) that minimizes the sum of squares \((y_i- X_i\hat{\beta})^{2}\). If we are trying to predict an outcome using other variables, we want to do so in such a way as to minimize the error of our prediction.

Residuals: \(r_i= y_i- X_i\hat{\beta}\) are the differences between the data and the fitted values. As a byproduct of the least squares estimation of \(\beta\), the residuals ri will be uncorrelated with all the predictors in the model.

Residual standard deviation: \(\hat{\sigma}\) summarizes the scale of the residuals. For example, in the test scores example, \(\hat{\sigma}\) = 18, which tells us that the linear model can predict children’s test scores to about an accuracy of 18 points. It’s like a measure of the average distance each observation falls from its prediction from the model. We are typically interested in it for its own sake—as a measure of the unexplained variation in the data—or because of its relevance to the precision of inferences about the regression coefficients \(\beta\).

example

GENERALIZED LINEAR MODELS

generalize the linear regression strategy—replace a parameter describing the shape of the likelihood with a linear model—to probability distributions other than the Gaussian.

Steps:

1.We need a linear predictor of the same form as in linear regression \(\beta X\). Such a linear predictor can generate any type of number as a prediction: positive, negative, or zero

2.We choose a suitable distribution for the type of data we are predicting (normal for any number, gamma for positive numbers, binomial for binary responses, Poisson for counts)

3.We create a link function which maps the mean of the distribution onto the set of all possible linear prediction results, which is the whole real line (-∞, ∞)

4.The inverse of the link function takes the linear predictor to the actual prediction

LOGISTIC REGRESSION

outcome

binary (0,1)

distribution

binomial: \(y_i \to Binomial(n, p_i)\)

model

\(f(\hat{p_i})=\alpha +\beta(x_i-\bar{x})\)

linear predictor: \(\eta_i\) = \(logit(\hat{p_i}) = log(p_i/(1-p_i)) = log(ODDS) =\alpha +\beta x_i\)

assumptions

  • linearity: \(logit(\hat{p_i})\) is a linear function of the predictors = it is linear in the coefficients
  • independence: the different observations are statistically independent
  • variance function: \(\sigma^2 = p(1-p)\)
  • binomial: the error distribution is binomial

parameter estimation

MAXIMUM LIKELIHOOD ESTIMATION

The likelihood is the pdf of the data thought of as a function of the parameters for data already observed (the data is fixed, the values of the parameters vary accordingly).

Maximum likelihood (ML) is an established method of estimating the parameters in a data analysis problem.

Binomial distribution pmf: function of x, given a certain n and p :\(f ( x | n , p ) = \begin{pmatrix} n \\ x \end{pmatrix} p^x (1-p)^{n-x}\)

Likelihood function: function of p, given a certain n and x (given by the data) \(f ( p | n , x ) =\begin{pmatrix} n \\x \end{pmatrix} p^x (1-p)^{n-x}\)

Log of the Likelihood function (omitting the first term because it doesn’t depend on p): \(g(p)= x ln(p) + (n-x) ln(1-p)\)

Derivative of the Log of the Likelihood function \(g'(p)= (x/p) - (n-x)/(1-p) = 0\)

The Maximum likelihood estimator is: \(\hat{p} = x/n\)

The likelihood is a graph of the value of the different values of p for a given value of n and x

Likelihood of the ith observation

\(p_{i}^{x_{i}}(1-p_{i})^{1-x_{i}}\)

So for \(y_1, y_2 ... y_n \to b(m, p_i)\)

The Maximum likelihood estimator is: \(\hat{p} = y_i/m\)

Likelihood = product of the likelihoods of the m individual i observations and n parameterns

\(f ( p_i | m , y_i ) = \begin{pmatrix} m \\ y_i \end{pmatrix} (y_i/m)^{y_i} (1-y_i/m)^{m-y_i}\)

Log of the Likelihood function: \(g(p_i)= y_i ln(y_i/m) + \sum(m-y_i) ln(1-y_i/m)\)

The Log likelihood is maximized with respect to \(\beta_{0}\) and \(\beta_{1}\) that are chosen so that:

\(p_{i}\) is large when \(x_{i} = 1\) because we want \(\sum_{x_{i} = 1} ln (p_{i})\) to be big

\(p_{i}\) is small when \(x_{i} = 0\) because we want \(\sum_{x_{i} = 0}ln(1-p_{i})\) to be big

Because \(p_{i}^{x_{i}}(1-p_{i})^{1-x_{i}}\) then

\(x_{i} = 0 \rightarrow (1-p_{i})\)

\(x_{i} = 1 \rightarrow p_{i}\)

interpretation of coefficients

interpretation of coefficients as probabilities

The curve of the logistic function requires us to choose where to evaluate changes, if we want to interpret on the probability scale. The mean of the input variables in the data is often a useful starting point.

EXAMPLE: Pr(Bush support) = invlogit (-1.40 + 0.33 · income)

\(\beta_0\):

For this dataset, income is on a 1–5 scale. We can evaluate Pr(Bush support) at the central income category (3) and get inverse logit(-1.40 + 0.33 · 3) = 0.40.

\(\beta_{income}\): A difference of 1 in income (on this 1–5 scale) corresponds to a positive difference of 0.33 in the logit probability of supporting Bush.

  • evaluate how the probability differs with a unit difference in x near the central value:

In this example: \(\bar{x}= 3.1\), so we can evaluate the logistic regression function at x = 3 and x = 2 ( 3 - 2 = 1 unit difference in x).

inverse logit(-1.40 + 0.33 · 3) - inverse logit(-1.40 + 0.33 · 2) = 0.08

A difference of 1 in income category corresponds to a positive difference of 8% in the probability of supporting Bush.

  • compute the derivative of the logistic curve at the central value:

derivative of the inverse logit (\(\alpha +\beta x_i\)) = \(\frac{df}{dx} e^{(\alpha +\beta x_i)} / 1 + e^{(\alpha +\beta x_i)} = \beta e^{(\alpha +\beta x_i)}/(1 + e^{(\alpha +\beta x_i)})^2\)

In this example:

The mean of x= \(\bar{x}= 3.1\).

The value of the linear predictor at the central value: -1.40 + 0.33 · 3.1 = -0.39.

The slope of the curve—the “change” in Pr(y = 1) per small unit of “change” in x is the derivative of the inverse logit at the central value: \(\frac{df}{dx} e^{(-1.40 + 0.33 · 3.1)} / 1 + e^{(-1.40 + 0.33 · 3.1)}= 0.33 e^{(-0.39)} / (1 + e^{(-0.39)})^2= 0.13\)

  • divide by 4 rule:

The logistic curve is steepest at its center, at which point \(\alpha +\beta x_i = 0\) so that inverse logit (\(\alpha +\beta x_i\)) = 0.5

The slope of the curve—the derivative of the logistic function—is maximized at this point and attains the value \(\beta e^{(0)} / (1 + e^{(0)})^2= \beta/4\).

\(\beta/4\) is the maximum difference in Pr(y = 1) corresponding to a unit difference in x. As a rule of convenience, we can take logistic regression coefficients (other than the constant term) and divide them by 4 to get an upper bound of the predictive difference corresponding to a unit difference in x. This upper bound is a reasonable approximation near the midpoint of the logistic curve, where probabilities are close to 0.5.

In this example: 0.33/4 = 0.08. A difference of 1 in income category corresponds to no more than an 8% positive difference in the probability of supporting Bush.

The results from these 3 methods 0.08, 0.13 and 0.08 are close to each other. In some cases where a unit difference is large, the differencing and the derivative can give slightly different answers. They will always be the same sign, however.

interpretation of coefficients as odds ratios

The “odds” of an event are just the probability it happens divided by the probability it does not happen: \((p_i/(1-p_i))\)

The ratio of two odds is an odds ratio: \((p_1/(1-p_1))/(p_2/(1-p_2))\)

An advantage of working with odds ratios (instead of probabilities) is that it is possible to keep scaling up odds ratios indefinitely without running into the boundary points of 0 and 1.

\(log(P(y=1|x)/P(y=0|x))= log ODDS= \alpha +\beta x_i\)

Adding 1 to x (that is, changing x to x+1) has the effect of adding \(\beta\) to both sides of the equation. \(log(P(y=1|x)/P(y=0|x)) + \beta = log ODDS + \beta= \alpha +\beta x + \beta = \alpha +\beta (x+1)\)

Exponentiating both sides, the odds are then multiplied by \(e^{\beta}\).

\(e^{log ODDS + \beta}= e^{\alpha +\beta (x + 1)}\)

\(ODDS e^{\beta}= e^{\alpha +\beta (x + 1)}\)

Exponentiated logistic regression coefficients can be interpreted as odds ratios.

EXAMPLE: if \(\beta= 0.2\), then a unit difference in x corresponds to a multiplicative change of \(e^{0.2} = 1.22\) in the odds (for example, changing the odds from 1 to 1.22, or changing p from 0.5 to 0.55).

\(\beta_0\) = intercept: baseline log odds. This is meaningful only for the specific population at hand (mainly in cohort studies). EXAMPLE: If we have a case control study with 50% cases and 50% controls, and the population has 4% cases, then clearly the baseline risk for the case control study has no relevance to the population.

\(\beta_i\): holding all other factors constant:

  • continuous variable: log of the odds ratio for a unit change in the variable (because a difference of logs is the log of the ratio)

  • categorical variable: change in the log odds ratio from the baseline level

\(\beta_{A:B}\) = interaction: holding all other factors constant:

the effect of A depends on the level of B

\(\eta_i\) = \(logit(\hat{p_i}) = log(p_i/(1-p_i)) = log(ODDS) =\alpha +\beta_A x_A + \beta_B x_B + \beta_{A:B} x_{A:B}\)

when \(x_B= 0\) the effect of A is \(\beta_A\)

when \(x_B= 1\) the effect of A is \(\beta_A + \beta_{A:B}\)

EXAMPLE: in study about distribution of insulin-like growth factor (IGF-1). menarche ~ age + tanner

library("ISwR")

data(juul)

juul1 <- subset(juul,age > 8 & age < 20 & complete.cases(menarche))

juul1$menarche <- factor(juul1$menarche,labels=c("No","Yes")) 
juul1$tanner <- factor(juul1$tanner) 

attach(juul1)

juul1.glm <- glm(menarche~age+tanner,binomial,data=juul1) 
summary(juul1.glm)
## 
## Call:
## glm(formula = menarche ~ age + tanner, family = binomial, data = juul1)
## 
## Deviance Residuals: 
##      Min        1Q    Median        3Q       Max  
## -2.56180  -0.12461   0.02475   0.08055   2.86120  
## 
## Coefficients:
##             Estimate Std. Error z value Pr(>|z|)    
## (Intercept) -13.7758     2.7630  -4.986 6.17e-07 ***
## age           0.8603     0.2311   3.723 0.000197 ***
## tanner2      -0.5211     1.4846  -0.351 0.725609    
## tanner3       0.8264     1.2377   0.668 0.504313    
## tanner4       2.5645     1.2172   2.107 0.035132 *  
## tanner5       5.1897     1.4140   3.670 0.000242 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## (Dispersion parameter for binomial family taken to be 1)
## 
##     Null deviance: 604.19  on 435  degrees of freedom
## Residual deviance: 106.60  on 430  degrees of freedom
##   (83 observations deleted due to missingness)
## AIC: 118.6
## 
## Number of Fisher Scoring iterations: 8

\(\beta age\)

Log odds ratio for one year increase in age is 0.8603, holding tanner constant \(\to\) Odds ratio is exp(0.8603) = 2.364

Log odds ratio for a two year increase in age is (2)(0.8603) = 1.7206 \(\to\) Odds ratio is exp(1.7206) = 5.588

\(\beta tanner4\)

  • Log odds ratio for tanner 4 vs. tanner 1 is 2.5645, holding age constant

Odds ratio is exp(2.5645) = 12.994

This means the odds of having menarche are 13 times higher for girls with tanner4 than with tanner1.

  • Log odds ratio for tanner 4 vs. tanner 3 is 2.5645 – 0.8264 = 1.7381

Odds ratio is exp(1.7381) = 5.687

inference

confidence intervals: to calculate a confidence interval you need to know the standard deviation. To know the standard deviation you need to know the variance, which we can obtain from the variance-covariance matrix.

A B C
A VAR(A) COV(A,B) COV(C,A)
B COV(B,A) VAR(B) COV(C,B)
C COV(A,C) COV(B,C) VAR(C)
  • confidence interval for one variable :

log odds confidence interval:\(\beta_i \pm z_{0.025} \sqrt{Var(\beta_i)}\)

odds ratio confidence interval:\(e^{\beta_i \pm z_{0.025} \sqrt{Var(\beta_i)}}\)

  • confidence interval between two levels of the same variable :

log odds confidence interval: \((\beta_C - \beta_B) \pm 1.96 \sqrt{Var(B) + Var(C) - 2COV(B,C)}\)

odds ratio confidence interval: \(e^{(\beta_C - \beta_B) \pm 1.96 \sqrt{Var(B) + Var(C) - 2COV(B,C)}}\)

Because: If X and Y are random variables then \(V(X-Y) = V(X) + V(Y)- 2Cov(X,Y)\)

EXAMPLE: Confidence interval of the estimated log odds between tanner4 and tanner5

coefficient matrix

c1 <- coef(juul1.glm)
c1
## (Intercept)         age     tanner2     tanner3     tanner4     tanner5 
## -13.7758129   0.8603095  -0.5210667   0.8264390   2.5645049   5.1896586

variance_covariance matrix

v1 <- vcov(juul1.glm)
v1
##             (Intercept)         age     tanner2    tanner3    tanner4
## (Intercept)  7.63420854 -0.59398971 -0.08627975  0.2184034  0.4414426
## age         -0.59398971  0.05338584 -0.08439333 -0.1117773 -0.1318233
## tanner2     -0.08627975 -0.08439333  2.20415172  1.2019693  1.2336584
## tanner3      0.21840340 -0.11177725  1.20196929  1.5319140  1.3012763
## tanner4      0.44144258 -0.13182328  1.23365842  1.3012763  1.4816528
## tanner5      0.69730303 -0.15481918  1.27001076  1.3494243  1.4075578
##                tanner5
## (Intercept)  0.6973030
## age         -0.1548192
## tanner2      1.2700108
## tanner3      1.3494243
## tanner4      1.4075578
## tanner5      1.9993267

We want to compare tanner4 to tanner5, so we only care about the last 2 columns.

#We set the other 4 columns to 0. We want to substract tanner4 from tanner5, so we multiply tanner4 by -1 and tanner5 by 1.

#in vector form this will multiply the rows of the vcv matrix 

b1 <- c(0,0,0,0,-1,1)
b1
## [1]  0  0  0  0 -1  1
#in transposed vector form this will multiply the columns of the vcv matrix 
t(b1) 
##      [,1] [,2] [,3] [,4] [,5] [,6]
## [1,]    0    0    0    0   -1    1

multiplying t(b1) * c1 is the same as doing 5.1897 − 2.5645 = 2.6252

this is the difference in the log odds between tanner4 and tanner5

t(b1) %*% c1
##          [,1]
## [1,] 2.625154

to calculate the ci we need the variance, which we extract like so:

we multiply the cols and rows by (0,0,0,-1,1) in order to end up with the bottom right corner of 4 numbers

1.4816528 1.4075578

1.4075578 1.9993267

var of the difference= var(x) + var (y) - 2 cov(x,y) = 1.4816528 +1.9993267 -2 *( 1.4075578)

 t(b1)%*% v1 %*% b1
##           [,1]
## [1,] 0.6658638

0.6658638 is the variance. to calculate the ci we need the se, so sqrt(0.6658638)

ci for the log odds ratio 2.625154 ± (1.960)√0.6658638 = (1.025, 4.224)

ci for the odds ratio (2.787, 68.33)

  • confidence interval of an interaction

log odds confidence interval: \((\beta_A + \beta_{A:B}) \pm 1.96 \sqrt{Var(A) + Var(A:B) - 2COV(A,A:B)}\)

odds ratio confidence interval: \(e^{(\beta_A + \beta_{A:B}) \pm 1.96 \sqrt{Var(A) + Var(A:B) - 2COV(A,A:B)}}\)

model comparison

deviance : twice the difference between the best possible log likelihood and the log likelihood under the model.

The differences in deviance are assessed using the chi‐squared distribution with degrees of freedom equal to the number of parameters omitted between the larger and smaller model. This test is asymptotic, that is, it gets more accurate as n increases.

smaller values are better.

EXAMPLE: \(y_{i} = y_{1}, y_{2}...y_{n}\) ~ bin(m, \(p_{i}\))

The best fit possible is to set \(\hat{p_{i}} = y_{i}/m\)

Best likelihood: has the highest possible value for the likelihood and uses n parameters (all n of the \(y_{i}\)s): \(\prod\begin{pmatrix} m \\y_{i} \end{pmatrix} (y_{i}/m)^{y_{i}} (1-y_{i}/m)^{m-y_{i}}\)

Best log likelihood: \(y_{i} ln(y_{i}/m) +(m-y_{i})ln (1-y_{i}/m)\)

If instead we use a a statistical model using fewer parameters that predicts \(\hat{p_{i}}\) , where \(\hat{\mu_{i}}=m \hat{p_{i}}\)

Model likelihood: maximized by choosing the coefficients: \(\prod\begin{pmatrix} m \\y_{i} \end{pmatrix} (\hat{\mu_{i}}/m)^{y_{i}} (1-\hat{\mu_{i}}/m)^{m-y_{i}}\)

Model log likelihood: \(y_{i} ln(\hat{\mu_{i}}/m) +(m-y_{i})ln (1-\hat{\mu_{i}}/m)\)

Deviance= \(2(y_{i} ln(y_{i}/m) +(m-y_{i})ln (1-y_{i}/m) - (y_{i} ln(\hat{\mu_{i}}/m) +(m-y_{i})ln (1-\hat{\mu_{i}}/m)) ) = 2\sum[(y_{i} ln(y_{i}/\hat{\mu_{i}}) + (m-y_{i})ln((m- y_{i})/(m- \hat{\mu_{i}}))]\)

the farther \(y_{i}\) is from \(\hat{\mu_{i}}\), the deviance is farther from 0 \(\rightarrow y_{i}/\hat{\mu_{i}}\) becomes farther from 1 and because ln(1)= 0

Null Model:

all the \(\hat{p_{i}}\) are the same and can the maximum likelihood estimator is

\(\hat{p}= \sum y_{i}/mn\) and \(\hat{\mu}= m\hat{p}\)

POISSON REGRESSION

outcome

count data (0,+∞). positive numbers.

Differences between the binomial and Poisson models: The Poisson model is similar to the binomial model for count data but is applied in slightly different situations: • If each data point yi can be interpreted as the number of “successes” out of ni trials, then it is standard to use the binomial/logistic model or its overdispersed generalization. • If each data point yi does not have a natural limit—it is not based on a number of independent trials—then it is standard to use the Poisson/logarithmic regression model (as described here) or its overdispersed generalization.

distribution

poisson \(y_i \to Poisson(\theta_i)\)

mean = variance = \(\theta\)

model

\(\theta_i=e^{\beta_0 +\beta_ix_i}\)

In the general Poisson regression model, we think of yi as the number of cases in a process with rate \(\theta_i\) and exposure \(u_i\).

\(y_i \to Poisson(\theta_i, u_i)\)

assumptions

  • linearity: \(log(\theta)\) is a linear function of the predictors
  • independence: the different observations are statistically independent
  • variance function: mean = variance = \(\theta\)

parameter estimation

MLE = \(\hat{\theta}= y\)

interpretation of coefficients

The coefficients \(\beta\) can be exponentiated and treated as multiplicative effects.

The regression coefficients summarize the associations between the predictors and \(\theta\)

EXAMPLE \(y_i \to Poisson(e^{2.8+ 0.012X_{i1} - 0.20X_{i2}})\)

Traffic accident model of the rate of traffic accidents per vehicle = \(\theta\) :Xi1 is average speed (in miles per hour, or mph) on the nearby streets and Xi2 = 1 if the intersection has a traffic signal or 0 otherwise

\(\beta_0\) The constant term gives the intercept of the regression, that is, the prediction if Xi1 = 0 and Xi2 = 0. Since this is not possible (no street will have an average speed of 0), we will not try to interpret the constant term.

\(\beta_1\) The coefficient of Xi1 is the expected difference in y (on the logarithmic scale) for each additional mph of traffic speed. Thus, the expected multiplicative increase is \(e^{0.012} = 1.012\), or a 1.2% positive difference in the rate of traffic accidents per mph. Since traffic speeds vary by tens of mph, it would actually make sense to define Xi1 as speed in tens of mph, in which case its coefficient would be 0.12, corresponding to a 12% increase (more precisely, e0.12 = 1.127: a 12.7% increase) in accident rate per ten mph.

\(\beta_2\) The coefficient of Xi2 tells us that the predictive difference of having a traffic signal can be found be multiplying the accident rate by \(e^{0.20} = 0.82\) yielding a reduction of 18% (1-0.82= 18).

As with regression models in general, each coefficient is interpreted as a comparison in which one predictor differs by one unit while all the other predictors remain at the same level,

offset In most applications of Poisson regression, the counts can be interpreted relative to some baseline or “exposure,” for example, the number of vehicles that travel through the intersection. \(y_i \to Poisson(\theta_i, u_i)\) .Putting the logarithm of the exposure into the model as an offset is equivalent to including it as a regression predictor, but with its coefficient fixed to the value 1. In this way the rate is proportional to the exposure.

\(y_i \to Poisson(\theta_i, u_i)\)

\(log(\theta_i)= \beta_0 +\beta_ix_i + log(u_i)\)

\(\theta_i=e^{\beta_0 +\beta_ix_i + log(u_i)} = e^{\beta_0 +\beta_ix_i}e^{log(u_i)}= e^{\beta_0 +\beta_ix_i}u_i\)

overdispersion

Under the Poisson distribution the variance equals the mean—that is, the standard deviation equals the square root of the mean.

standardized residuals: \(z_i= y_i-\hat{y_i}/sd(\hat{y_i})= y_i-u_i\hat{\theta_i} /sd(u_i\hat{\theta_i})\)

If the Poisson model is true, then the zi’s should be approximately independent, each with mean 0 and standard deviation 1. If there is overdispersion, however, we would expect the zi’s to be larger, in absolute value, reflecting the extra variation beyond what is predicted under the Poisson model.

overdispersion test: compute the sums of squares of the standardized residuals \(\sum_{i=1}^n z_i^2\) and compare to the Chi-square distribution with degrees of freedom n-k (using n-k rather than n degrees of freedom to account for the estimation of k regression coefficients)

estimated overdispersion: \(1/(n-k) \sum_{i=1}^n z_i^2\)

EXAMPLE: the classical Poisson regression for the police stops has n = 225 data points and k = 77 linear predictors. \(\sum_{i=1}^n z_i^2\) = 2700 \((n-k)\) = 148

The estimated overdispersion factor is 2700/148 = 18.2, and the p-value is 1. indicating that the probability is essentially zero that a random variable from a +2148 distribution would be as large as 2700. In summary, the police stops data are overdispersed by a factor of 18, which is huge—even an overdispersion factor of 2 would be considered large—and also statistically significant.

adjust for overdispersion:

  • multiply all regression standard errors by the sqrt(overdispersion factor) EXAMPLE: \(\sqrt{18.2}= 4.3\)

  • fit overdispersed model: quasipoisson or negative binomial

NEGATIVE BINOMIAL

outcome

overdispersed count data (0,+∞). positive numbers.

any count-data model for which the variance of the data is \(\omega\) times the mean, reducing to the Poisson if \(\omega\) = 1.

distribution

negative binomial \(y_i \to negative binomial (\theta_i, \omega)\)

mean = \(u_i\theta= u_ie^{\beta X_i}\) = a/b

overdispersion= \(\omega\) = 1 + 1/b

the negative-binomial distribution is conventionally expressed not based on its mean and overdispersion but rather in terms of parameters a and b where the mean of the distribution is a/b and the overdispersion is 1 + 1/b. One must check the parameterization when fitting such models, and it can be helpful to double-check by simulating datasets from the fitted model and checking that they look like the actual data

MULTILEVEL MODELS

EXAMPLE: estimating the distribution of radon levels of the houses within each of the 85 counties in Minnesota

no predictors

complete pooling

\(\bar{y}_{all}\): Average that completely pools data across all counties. This ignores variation between counties in radon levels.

no pooling

\(\bar{y}_{j}\): Average of the observations in each county. No-pooling analysis overfits the data within each county.

partial pooling

Average log radon level \(\alpha_j\) among all the houses in county j, for which all we have available are a random sample of size \(n_j\). It’s like a weighted average of \(\bar{y}_{j}\) and \(\bar{y}_{all}\) which reflects the relative amount of information available about the individual county, on one hand, and the average of all the counties, on the other.

  • if \(n_j = 0\) then \(\alpha_j = \bar{y}_{all}\)

  • if \(n_j \to \infty\) then \(\alpha_j = \bar{y}_{j}\)

with predictors

EXAMPLE: logarithm of the home radon measurement versus floor of measurement3 for houses sampled from eight of the 85 counties in Minnesota.

complete pooling

Classical regression completely ignoring the group information, a single model fit to all the data.

\(y_i= \alpha +\beta x_i + \epsilon_i\) or y ~ x

\(\alpha_{j}\) is fixed at the average for the whole data set \(\alpha\)

This analysis ignores any variation in average radon levels between counties.

no pooling

Can refer to

  • Separate models: a separate classical regression in each group: \(y_j= \alpha_{j} +\beta x_i + \epsilon_i\)

  • No-pooling model: a single classical regression that includes group indicators (but no group-level predictors) but with no model for the group coeðcients: \(y_i= \alpha_{j[i]} +\beta x_i + \epsilon_i\) where j[i] is the county correspoinding to house i.

\(y_i= \alpha_{j[i]} +\beta x_i + \epsilon_i\) is expressed in lmer as y ~ x + factor(county) - 1)

where we add -1 to the regression formula to remove the constant term, so that all 85 counties are included.

This version of “no pooling” does not pool the estimates for the intercepts \(\alpha_{j}\) but it does completely pool estimates for any slope coefficients (they are forced to have the same value across all groups) and also assumes the residual variance is the same within each group.

\(\alpha_{j}\) is set to the classical least squares estimates, which correspond to the fitted intercepts in a model run separately in each county. The constraint is that the slope coeffcient equals \(\beta\) in all models.

This analysis is very dependent on the number of observations per county.

partial pooling

\(y_i \sim N(\alpha_{j[i]} +\beta x_i, \sigma_y^2)\)

\(\alpha_{j} \sim N(\mu_{\alpha}, \sigma_{\alpha}^2)\)

\(\alpha_{j}\) has a “soft-constraint” in the form of a probability distribution, that has the effect of pulling the estimates of \(\alpha_{j}\) toward the mean level \(\mu_{\alpha}\)

  • if \(\sigma_{\alpha} \to 0\) then the soft-constraints pull the estimate to 0 \(\alpha_j = \alpha\) = complete-pooling estimate.

  • if \(\sigma_{\alpha} \to \infty\) then soft constraints do nothing \(\alpha_j = \alpha_j\) = no pooling estimate.

There is strong pooling in counties with small sample sizes, and only weak pooling in counties containing many measurements.

WHEN TO USE MULTILEVEL MODELS

Multilevel model is most important when it is close to complete pooling, when \(\sigma_{\alpha}\) is small and the groups are similar to each other. When \(\sigma_{\alpha}\) is large, so that groups vary greatly, multilevel modeling is not much better than simple no-pooling estimation.However the multilevel estimate can be close to complete pooling for groups with small sample size and close to no pooling for groups with large sample size, automatically performing well for both sorts of group.

How many groups? When the number of groups is small, it is difficult to estimate the between-group variation and, as a result, multilevel modeling often adds little in such situations, beyond classical no-pooling models. When \(\sigma_{\alpha}\) cannot be estimated well, it tends to be overestimated, and so the partially pooled estimates are close to no pooling. For 1-2 groups multilevel modeling reduces to classical regression